Substituted pyrazoles

ABSTRACT

Substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them to treat, for example, autoimmune diseases mediated by cathepsin S.

This application is a division of U.S. patent application Ser. No.09/928,122, filed Aug. 10, 2001, that is incorporated herein byreference in its entirety, and application Ser. No. 09/928,122 in turnclaims the benefit under 35 U.S.C. § 119(e) of U.S. ProvisionalApplication Ser. No. 60/225,138, filed on Aug. 14, 2000.

FIELD OF THE INVENTION

This invention relates to a series of substituted pyrazoles,pharmaceutical compositions containing these compounds, andintermediates used in their manufacture, and methods of using them.

BACKGROUND OF THE INVENTION

Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papain familyfound primarily in lysosomes (Bromme, D.; McGrath, M. E. High LevelExpression and Crystallization of Recombinant Human Cathepsin S. ProteinScience 1996, 5, 789-791).

The role of cathepsin S in the immune response is anticipated by itstissue distribution: cathepsin S is found primarily in lymphatictissues, lymph nodes, the spleen, B lymphocytes, and macrophages(Kirschke, H. Chapter 211. Cathepsin S. In Handbook of ProteolyticEnzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J. F., Eds. SanDiego: Academic Press, 1998. pp. 621-624.). Cathepsin S inhibitors havebeen shown in animal models to modulate antigen presentation and areeffective in an animal model of asthma (Riese, R. J.; Mitchell, R. N.;Villadangos, J. A.; Shi, G.-P.; Palmer, J. T.; Karp, E. R.; De Sanctis,G. T.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Activity RegulatesAntigen Presentation and Immunity. J. Clin. Invest. 1998, 101, 2351-2363and Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.;Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A. Cathepsin SRequired for Normal MHC Class II Peptide Loading and Germinal CenterDevelopment. Immunity 1999, 10, 197-206.).

Mice in which the gene encoding cathepsin S has been knocked out areless susceptible to collagen-induced arthritis and their immune systemshave an impaired ability to respond to antigens (Nakagawa, T. Y.;Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.; Stock,J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S. R. M.;Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y. Impaired InvariantChain Degradation and Antigen Presentation and DiminishedCollagen-induced Arthritis in Cathepsin S Null Mice. Immunity 1999, 10,207-217).

These data demonstrate that compounds that inhibit the proteolyticactivity of human cathepsin S should find utility in the treatment ofchronic autoimmune diseases including, but not limited to, lupus,rheumatoid arthritis, and asthma; and have potential utility inmodulating the immune response to tissue transplantation.

There are a number of cathepsin S inhibitors reported in the literature.The most important patents are listed below.

Certain dipeptidyl nitriles are claimed by Novartis as cathepsin Sinhibitors in: Altmann, et. al. WO-99/24460.

Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) as cysteineprotease (including cathepsin S) inhibitors in: Palmer, et. al. U.S.Pat. No. 5,976,858.

Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteineprotease (including cathepsin S) inhibitors in: Palmer, et. al. U.S.Pat. No. 5,776,718 (assigned to Arris, now Axys) & Klaus, et. al. U.S.Pat. No. 6,030,946 (assigned to Axys).

Compounds somewhat similar to those of the present invention aredescribed in the following references.

Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. Med.Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant. Struct.-Act.Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in U.S. Pat.No. 4,500,525 (1985)) have described bicyclic pyrazoles of the typeshown below. R never contains a heterocyclic ring and no proteaseinhibitor activity is ascribed to these molecules; they are described asα1-adrenergic receptor modulators.

Shutske, et. al. claim the bicylic pyrazoles below. The pyridine ring isaromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer, J. D.U.S. Pat. No. 5,264,576 (1993)). Although reference is made to R being alinker to a heterocycle, the claims specify only R=hydrogen. Thecompounds are referred to as serotonin reuptake inhibitors.

The compound2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidineis known from EP-382637, which describes pyrimidines having anxiolyticproperties. This compound and analogs are further described in EP-502786as cardiovascular and central nervous system agents. Pharmaceuticalformulations with such compounds are disclosed in EP-655248 for use inthe treatment of gastric secreation and as anti-ulcer agents. WO-9721439describes medicaments with such compounds for treatingobsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesisand motion sickness.

The compounds5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole,in particular the hydrochloride salts thereof, are known from WO-9853940and CA 122:314528, where these and similar compounds are described askinase inhibitors in the former reference and possessing affinity forbenzodiazepine receptors in the latter reference.

SUMMARY OF THE INVENTION

The present invention concerns compounds which can be represented byformula (I):

wherein:

-   R¹ is hydrogen, azido, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,    C₂₋₅ alkenyl, cyano, nitro, R⁷R⁸N, C₂₋₈ acyl, R⁹OC═O, R¹⁰R¹¹NC═O, or    R¹⁰R¹¹NSO₂; or R¹ is taken together with W as described below;-   R² is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅    haloalkyl, cyano, or R⁴⁸R⁴⁹N;    -   alternatively, R¹ and R² can be taken together to form an        optionally substituted 5- to 7-membered carbocyclic or        heterocyclic ring, which ring may be unsaturated or aromatic;-   each of R³ and R⁴ is independently hydrogen or C₁₋₅ alkyl;-   each of R⁵ and R⁶ is independently hydrogen, C₁₋₅ alkyl, C₂₋₅    alkenyl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, halogen, or a 4-7 membered    carbocyclyl or heterocyclyl;-   alternatively, R⁵ and R⁶ can be taken together to form an optionally    substituted 5- to 7-membered carbocyclic or heterocyclic ring, which    ring may be unsaturated or aromatic, and may be optionally    substituted with between one and three substituents independently    selected from halo, cyano, amino, nitro, R⁴⁰, R⁴⁰O—, R⁴⁰S—,    R⁴⁰O(C₁₋₅ alkylene)-, R⁴⁰O(C═O)—, R⁴⁰(C═O)—, R⁴⁰(C═S)—, R⁴⁰(C═O)O—,    R⁴⁰O(C═O)(C═O)—, R⁴⁰SO₂, NHR⁶²(C═NH)—, NHR⁶²SO₂—, and NHR⁶²(C═O)—;-   R⁴⁰ is H, C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl, benzyl, phenethyl, C₁₋₅    heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, amino, or mono- or    di(C₁₋₅ alkyl)amino, or R⁵⁸OR⁵⁹—, wherein R⁵⁸ is H, C₁₋₅ alkyl, C₂₋₅    alkenyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, or (C₁₋₅    heterocyclyl)C₁₋₆ alkylene and R⁵⁹ is C₁₋₅ alkylene, phenylene, or    divalent C₁₋₅ heterocyclyl; and-   R⁶² can be H in addition to the values for R⁴⁰;-   R⁷ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅    heterocyclyl, C₂₋₈ acyl, aroyl, R²⁷OC═O, R²⁸R²⁹NC═O, R²⁷SO, R²⁷S₂,    or-   R⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅    heterocyclyl;    -   alternatively, R⁷ and R⁸ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   R⁹ is C₁₋₅ alkyl, phenyl, naphthyl, or C₁₋₅ heterocyclyl;-   R²¹ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅    heterocyclyl, C₂₋₁₈ acyl, aroyl, R³⁰OC═O, R³¹R³²NC═O, R³⁰SO, R³⁰SO₂,    or R³¹R³²NSO₂;-   R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅    heterocyclyl;    -   alternatively, R²¹ and R²² can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   each of R²³, R²⁶, R²⁷, R³⁰, R³³, R⁴⁴, R⁴⁵, and R⁵⁰ is C₁₋₅ alkyl,    phenyl, naphthyl, or C₁₋₅ heterocyclyl;-   R²⁴ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅    heterocyclyl, C₂₋₈ acyl, aroyl, R³³OC═O, R³⁴R³⁵NC═O, R³³SO, R³³SO₂,    or R³⁴R³⁵NSO₂;-   R²⁵ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅    heterocyclyl;    -   alternatively, R²⁴ and R²⁵ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   each of R¹⁰ and R¹¹ is independently hydrogen, C₁₋₅ alkyl, C₂₋₅    alkenyl, phenyl, or C₁₋₅ heterocyclyl;    -   alternatively, R¹⁰ and R¹¹ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   each of R²⁸, R²⁹, R³¹, R³², R³⁴, R³⁵, R⁴⁶, R⁴⁷, R⁵¹ and R⁵² is    independently hydrogen, C₁₋₅ alkyl, phenyl, or C₁₋₅ heterocyclyl;    -   alternatively, R²⁸ and R²⁹, R³¹ and R³², R³⁴ and R³⁵, R⁴⁶ and        R⁴⁷, or R⁵¹ and R⁵², independently, can be taken together to        form an optionally substituted 4- to 7-membered heterocyclic        ring, which ring may be saturated, unsaturated or aromatic;-   n is 1 or 2;-   G represents C₃₋₆ alkenediyl or C₃₋₆ alkanediyl, optionally    substituted with hydroxy, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo,    hydroximino, CO₂R⁶⁰, R⁶⁰R⁶¹NCO₂, (L)-C₁₋₄ alkylene-, (L)-C₁₋₅    alkoxy, N₃, or [(L)-C₁₋₅ alkylene]amino;-   each of R⁶⁰ and R⁶¹ is independently hydrogen, C₁₋₅ alkyl, C₃₋₅    alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅ heterocyclyl;    alternatively, R⁶⁰ and R⁶¹ can be taken together to form an    optionally substituted 4- to 7-membered heterocyclic ring, which    ring may be saturated, unsaturated or aromatic;-   L is amino, mono- or di-C₁₋₁₅ alkylamino, pyrrolidinyl, morpholinyl,    piperidinyl, homopiperidinyl, or piperazinyl, where available ring    nitrogens may be optionally substituted with C₁₋₅ alkyl, benzyl,    C₂₋₅ acyl, C₁₋₅ alkylsulfonyl, or C₁₋₅ alkyloxycarbonyl;-   X is nitrogen or R¹²C;-   Y is nitrogen or R¹³C-   Z is nitrogen or R¹⁴C-   R¹² is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl,    cyano, nitro, R²¹R²²N, C₂₋₈ acyl, C₁₋₅haloalkyl, C₁₋₅ heterocyclyl,    (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R²³OC═O, R²³O(C═O)NH—, R²³SO,    R²²NHCO—, R²²NH(C═O)NH—, R²³(C₁₋₄ alkylene)NHCO—, R²³SO₂, or    R²³SO₂NH—;-   R¹³ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl,    cyano, nitro, R⁴²R⁴³N, C₂₋₈ acyl, C₁₋₅ haloalkyl, C₁₋₅ heterocyclyl,    (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R⁴⁴OC═O, R⁴⁴O(C═O)NH—, R⁴⁴SO,    R⁴³NHCO—, R⁴³NH(C═O)NH—, R⁴⁴(C₁₋₄ alkylene)NHCO—, R⁴⁴SO₂, or    R⁴⁴SO₂NH—;-   R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl,    cyano, nitro, R²⁴R²⁵N, C₂ acyl, C₁₋₅ haloalkyl, C₁₋₅ heterocyclyl,    (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R²⁶OC═O, R²⁶O(C═O)NH—, R²⁶SO,    R²⁵NHCO—, R²⁵NH(C═O)NH—, R²⁶(C₁₋₄ alkylene)NHCO—, R²⁶SO₂, or    R²⁶SO₂NH—;    -   alternatively, R¹² and R¹³ or R¹² and R² or R¹³ and R¹⁴ can be        taken together to form an optionally substituted 5- to        6-membered carbocyclic or heterocyclic ring, which ring may be        unsaturated or aromatic;-   Ar represents a monocyclic or bicyclic aryl or heteroaryl ring,    optionally substituted with between 1 and 3 substituents selected    from halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, azido,    nitro, R¹⁵R¹⁶N, R¹⁷SO₂, R¹⁷S, R¹⁷SO, R¹⁷OC═O, R¹⁵R¹⁶NC═O,    C₁₋₅haloalkyl, C₁₋₅ haloalkoxy, C₁₋₅haloalkylthio, and C₁₋₅    alkylthio;-   R¹⁵ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, C₁₋₅    heterocyclyl, C₂₋₈ acyl, aroyl, R⁵³OC═O, R⁵⁴R⁵⁵NC═O, R⁵³S, R⁵³SO,    R⁵³SO₂, or R⁵⁴R⁵⁵NSO₂;-   R¹⁶ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅    heterocyclyl;    -   alternatively, R¹⁵ and R¹⁶ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   each of R¹⁷ and R⁵³ is C₁₋₅ alkyl, phenyl, or C₁₋₅ heterocyclyl;-   each of R⁵⁴ and R⁵⁵ is independently hydrogen, C₁₋₅ alkyl, C₂₋₅    alkenyl, phenyl, benzyl, or C₁₋₅ heterocyclyl;    -   alternatively, R⁵⁴ and R⁵⁵ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;-   W represents SO₂, C═O, CHR²⁰, or a covalent bond; or W and R¹, taken    together with the 6-membered ring to which they are both attached,    form one of the following two formulae:

-   -   wherein X_(a) is O, S, or N; and X_(b) is O, S or SO₂;

-   R²⁰ is hydrogen, C₁₋₅ alkyl, phenyl, benzyl, naphthyl, or C₁₋₅    heterocyclyl;

-   R⁴² is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅    heterocyclyl, C₂₋₈ acyl, aroyl, R⁴⁵OC═O, R⁴⁶R⁴⁷NC═O, R⁴⁵SO, R⁴⁵SO₂,    or    -   R⁴⁶R⁴⁷NSO₂;

-   R⁴³ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅    heterocyclyl;    -   alternatively, R⁴² and R⁴³ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;

-   R⁴⁴ is C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl, naphthyl, or C₁₋₅    heterocyclyl;

-   R⁴⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅    heterocyclyl, C₂₋₈ acyl, aroyl, R⁵⁰OC═O, R⁵¹R⁵²NC═O, R⁵⁰SO, R⁵⁰SO₂,    or R⁵¹R⁵²NSO₂;

-   R⁴⁹ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅    heterocyclyl;    -   alternatively, R⁴⁸ and R⁴⁹ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic; and

-   wherein each of the above hydrocarbyl or heterocarbyl groups, unless    otherwise indicated, and in addition to any specified substituents,    is optionally and independently substituted with between 1 and 3    substituents selected from methyl, halomethyl, hydroxymethyl, halo,    hydroxy, amino, nitro, cyano, C₁₋₅ alkyl, C₁₋₅ alkoxy, —COOH, C₂₋₆    acyl, [di(C₁₋₄ alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄ alkyl)amino]C₂₋₅    alkyl-NH—CO—, and C₁₋₅ haloalkoxy;    or a pharmaceutically acceptable salt, ester, or amide thereof,    including a stereoisomeric form thereof.

The disclosed compounds are high-affinity inhibitors of the proteolyticactivity of human cathepsin S. For use in medicine, the preparation ofpharmaceutically acceptable salts of compounds of formula (I) may bedesirable.

Certain compounds of the present invention may have one stereogenic atomand may exist as two enantiomers. Certain compounds of the presentinvention may have two or more stereogenic atoms and may further existas diastereomers. It is to be understood by those skilled in the artthat all such stereoisomers and mixtures thereof in any proportion areencompassed within the scope of the present invention.

Another aspect of the invention provides pharmaceutical compositionscomprising a compound of formula (I) and a pharmaceutically acceptablecarrier. A further embodiment of the invention is a process for making apharmaceutical composition comprising mixing a disclosed compound asdescribed above, with a suitable pharmaceutically acceptable carrier.

The invention also contemplates pharmaceutical compositions comprisingmore than one compound of formula (I) and compositions comprising acompound of formula (I) and another pharmaceutically active agent.

The invention features a method of treating disorders or conditionsmediated by the cathepsin S enzyme, in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove. If more than one active agent is administered, thetherapeutically effective amount may be a jointly effective amount. Thecompounds described herein inhibit the protease activity of humancathepsin S, an enzyme involved in the immune response. In preferredembodiments, cathepsin S inhibition is selective. As such, the disclosedcompounds and compositions are useful in the prevention, inhibition, ortreatment of autoimmune diseases such as lupus, rheumatoid arthritis,and asthma, and for the prevention, inhibition, or treatment of tissuetransplant rejection.

Additional features and advantages of the invention will become apparentfrom the detailed description below, including examples, and theappended claims.

DETAILED DESCRIPTION OF THE INVENTION

The invention features pyrazole compounds of formula (I), methods ofmaking them, compositions containing them, and methods of using them totreat diseases and conditions, including those mediated by Cathepsin S.

A. TERMS

The following terms are defined below and by their usage throughout thisdisclosure.

“Alkyl” includes optionally substituted straight chain and branchedhydrocarbons with at least one hydrogen removed to form a radical group.Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl,octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Alkenyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon doublebond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenylincludes cycloalkenyl. Cis and trans or (E) and (Z) forms are includedwithin the invention.

“Alkynyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon triplebond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl doesnot include cycloalkynyl.

“Alkoxy” includes an optionally substituted straight chain or branchedalkyl group with a terminal oxygen linking the alkyl group to the restof the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and“sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygenatom of alkoxy with, respectively, NH (or NR), S, and SO₂. Heteroalkylincludes alkoxy, aminoalkyl, thioalkyl, and so on.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridge, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.

“Heterocyclyl” includes optionally substituted aromatic and nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unless otherwiseindicated, a heterocyclic radical may have a valence connecting it tothe rest of the molecule through a carbon atom, such as 3-furyl or2-imidazolyl, or through a heteroatom, such as N-piperidyl or1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g.,heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as thoseoptionally condensed with an optionally substituted carbocyclic orheterocyclic five- or six-membered aromatic ring. For example,“heteroaryl” includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed withan optionally substituted five- or six-memebered carbocyclic orheterocyclic aromatic ring. Said heterocyclic five- or six-memberedaromatic ring condensed with the said five- or six-membered aromaticring may contain 1, 2 or 3 nitrogen atoms where it is a six-memberedring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfurwhere it is a five-membered ring.

Examples of heterocyclyls include thiazoylyl, furyl, pyranyl,isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl,pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. Forexample, preferred heterocyclyls or heterocyclic radicals includemorpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino,cycloheptylimino, and more preferably, piperidyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl moiety attached to either a hydrogen atom(i.e., a formyl group) or to an optionally substituted alkyl or alkenylchain, or heterocyclyl.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably chloro or bromo as a substituent.

“Alkanediyl” or “alkylene” represents straight or branched chainoptionally substituted bivalent alkane radicals such as, for example,methylene, ethylene, propylene, butylene, pentylene or hexylene.

“Alkenediyl” represents, analogous to the above, straight or branchedchain optionally substituted bivalent alkene radicals such as, forexample, propenylene, butenylene, pentenylene or hexenylene. In suchradicals, the carbon atom linking a nitrogen preferably should not beunsaturated.

“Aroyl” refers to a carbonyl moiety attached to an optionallysubstituted aryl or heteroaryl group, wherein aryl and heteroaryl havethe definitions provided above. In particular, benzoyl isphenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which theyare attached may form an optionally substituted 4- to 7-, 5- to 7-, or a5- to 6-membered ring carbocyclic or heterocyclic ring, which ring maybe saturated, unsaturated or aromatic. Said rings may be as definedabove in the Summary of the Invention section. Particular examples ofsuch rings are as follows in the next section.

“Pharmaceutically acceptable salts, esters, and amides” includecarboxylate salts (e.g., C₁₋₈ alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃ alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

“Patient” or “subject” includes mammals such as humans and animals(dogs, cats, horses, rats, rabbits, mice, non-human primates) in need ofobservation, experiment, treatment or prevention in connection with therelevant disease or condition. Preferably, the patient or subject is ahuman.

“Composition” includes a product comprising the specified ingredients inthe specified amounts as well as any product which results directly orindirectly from combinations of the specified ingredients in thespecified amounts.

“Therapeutically effective amount” or “effective amount” means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

Concerning the various radicals in this disclosure and in the claims,three general remarks are made. The first remark concerns valency. Aswith all hydrocarbon radicals, whether saturated, unsaturated oraromatic, and whether or not cyclic, straight chain, or branched, andalso similarly with all heterocyclic radicals, each radical includessubstituted radicals of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context of the claims. Thecontext will indicate that the substituent is an alkylene or hydrocarbonradical with at least two hydrogen atoms removed (bivalent) or morehydrogen atoms removed (multivalent). An example of a bivalent radicallinking two parts of the molecule is G in formula (I) which links tworings.

Second, radicals or structure fragments as defined herein are understoodto include substituted radicals or structure fragments. Hydrocarbylsinclude monovalent radicals containing carbon and hydrogen such asalkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromaticor unsaturated), as well as corresponding divalent radicals such asalkylene, alkenylene, phenylene, and so on. Heterocarbyls includemonovalent and divalent radicals containing carbon, hydrogen, and atleast one heteroatom. Examples of monovalent heterocarbyls include acyl,acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl,dialkylamino, hydroxyalkyl, and so on. Using “alkyl” as an example,“alkyl” should be understood to include substituted alkyl having one ormore substitutions, such as between 1 and 5, 1 and 3, or 2 and 4substituents. The substituents may be the same (dihydroxy, dimethyl),similar (chlorofluoro), or different (chlorobenzyl- oraminomethyl-substituted). Examples of substituted alkyl includehaloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, perfluoromethyl, and 3-iodocyclopentyl),hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl,aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C₁₋₆ alkyl)aminogroup includes independently selected alkyl groups, to form, forexample, methylpropylamino and isopropylmethylamino, in additiondialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.

Third, only stable compounds are intended. For example, where there isan NR′R″ group, and R can be an alkenyl group, the double bond is atleast one carbon removed from the nitrogen to avoid enamine formation.Similarly, where a dashed line is an optional sp² bond, if it is absent,the appropriate hydrogen atom(s) is(are) included.

Preferred substitutions for Ar include methyl, methoxy, fluoromethyl,difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl,2-fluoroethyl, ethoxy, fluoro, chloro, and bromo, and particularlymethyl, bromo, chloro, perfluoromethyl, perfluoromethoxy, methoxy, andfluoro. Preferred substitution patterns for Ar or Ar₁ are 4-substitutedor 3,4-disubstituted phenyl.

Compounds of the invention are further described in the next section.

B. COMPOUNDS

The invention features compounds of formula (I) as described in theSummary section.

Preferred compounds include those wherein:

-   -   (a) R¹ is hydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl,        cyano, nitro, R⁷R⁸N, C₂₋₈ acyl, or R¹⁰R¹¹NSO₂;    -   (b) R¹ is halogen, cyano, nitro, R⁷R⁸N, or R¹⁰R¹¹NSO₂;    -   (c) R² is hydrogen;    -   (d) each of R³ and R⁴ is independently hydrogen or C₁₋₃ alkyl;    -   (e) one of R³ and R⁴ is hydrogen;    -   (f) each of R³ and R⁴ is hydrogen;    -   (g) one of R⁵ and R⁶ is hydrogen and the other is a 5-7 membered        carbocyclyl or heterocyclyl, optionally substituted;    -   (h) R⁵ and R⁶ taken together form a six-membered heterocyclyl;    -   (i) R⁵ and R⁵ taken together form pyridinyl, pyrimidinyl, or        piperazinyl, optionally N-substituted with R⁴⁰O(C═O)(C═O)—,        R⁴⁰SO₂, R⁴⁰NHCO₂, R⁴⁰(C═O)—, or R⁴⁰N(C═O)—;    -   (j) each of R⁷, R⁸, R²¹, R²², R²⁴, and R²⁵ is independently        hydrogen or C₁₋₅ alkyl; or, independently, each of R⁷ and R⁸,        R²¹ and R²², and R²⁴ and R²⁵ can be taken together to form an        optionally substituted 4- to 7-membered heterocyclic ring, which        ring may be saturated, unsaturated or aromatic;    -   (k) at least one of R⁷ and R⁸, R²¹ and R²², and R²⁴ and R²⁵,        taken together, is morpholinyl, piperidinyl, or pyrrolidinyl;    -   (l) R⁹, R²³, R²⁶, and R²⁷ are each independently C₁₋₅ alkyl;    -   (m) G is C₃₋₄ alkanediyl, optionally substituted with hydroxy,        (L)-C₁₋₅ alkyloxy-, or [(L)-C₁₋₅ alkylene]amino-;    -   (n) G is C₃ alkanediyl, optionally substituted with hydroxy,        (L)-C₁₋₅ alkyloxy-, or [(L)-C₁₋₅ alkylene]amino-;    -   (o) X is nitrogen;    -   (p) Y is CR¹³;    -   (q) Z is CR¹⁴;    -   (r) X is CH;    -   (s) R¹² is hydrogen, R²³O(C═O)NH—, R²²NH(C═O)NH—, R²³SO₂NH,        R²³SO, or R²³SO₂, and R¹³ is hydrogen, R⁴⁴O(C═O)NH—,        R⁴³NH(C═O)NH—, R⁴⁴SO₂NH, R⁴⁴SO, or R⁴⁴SO₂.    -   (t) R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, cyano,        nitro, R²⁶O(C═O)NH—, R²⁵NH(C═O)NH—, R²⁶SO₂NH, or R²⁴R²⁵N.    -   (u) R¹⁴ is halogen, R²⁶O(C═O)NH—, R²⁵NH(C═O)NH—, R²⁶SO₂NH, or        R²⁴R²⁵N; Ar represents a monocyclic ring, optionally substituted        with between 1 and 2 substituents selected independently from        halogen, C₁₋₅ alkyl, cyano, nitro, R¹⁵R¹⁶N, CF₃, and OCF₃;    -   (v) Ar is a six membered ring substituted with between 1 and 2        substituents selected from halo, CF₃, and OCF₃, said        substitutent or substitutents being at the 4-position or at the        3- and 4-positions, respectively;    -   (w) W is SO₂, C═O, or CHR²⁰;    -   (x) W is a covalent bond;    -   (y) W and R¹ taken together are formula (I)(a);    -   (z) W and R¹ taken together are formula (I)(b);    -   (aa) one of R³ and R⁴ is hydrogen; Ar represents a monocyclic        ring, optionally substituted with between 1 and 2 substituents        selected from halogen, C₁₋₅ alkyl, cyano, nitro, R¹⁵R¹⁶N, CF₃,        and OCF₃; R¹² is hydrogen, R²³SO, or R²³SO₂; R¹³ is hydrogen,        R⁴⁴SO, or R⁴⁴SO₂; R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅        alkyl, cyano, nitro, or R²⁴R²⁵N; and G is C₃₋₄ alkanediyl,        optionally substituted with hydroxy, C₁₋₃ alkyl, (L)-C₁₋₅        alkyloxy, or [(L)-C₁₋₅ alkylene]amino-;    -   (bb) each of R³ and R⁴ is hydrogen; Ar represents a six membered        ring, optionally substituted with between 1 and 2 substituents        selected from halogen, C₁₋₅ alkyl, cyano, nitro, R¹⁵R¹⁶N, CF₃,        and OCF₃; R¹² is hydrogen, R²³SO, or R²³SO₂; R¹³ is hydrogen,        R⁴⁴SO, or R⁴⁴SO₂; R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅        alkyl, cyano, nitro, or R²⁴R²⁵N; and G is C₃ alkanediyl,        optionally substituted with hydroxy, (L)-C₁₋₅ alkyloxy-, or        (L)-C₁₋₅ alkylamino;    -   (cc) Ar is phenyl; and    -   (dd) combinations of the above.

Specific preferred compounds include the examples herein, such as:1-[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-urea;1-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-urea;3-Amino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzoicacid methyl ester;3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine;1-[2-(4-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-3-chloro-phenyl]-3-methyl-urea;1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-carbamicacid methyl ester;1-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;2-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-3-nitro-benzoicacid methyl ester;1-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol;2-(4-{2-Hydroxy-3-[3-(4-iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrile;3-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide;2-(4-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile;2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile;1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone;1-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;2-(4-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrile;N-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide;3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide; and3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide.

Furthermore, preferred compounds include those wherein Ar is selectedfrom 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl,4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

More preferred compounds include the compounds in Examples 19, 27, and33.

Related Compounds

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, acids, hydrates or solvated forms thereof; maskedor protected forms; and racemic mixtures, or enantiomerically oroptically pure forms. Related compounds also include compounds of theinvention that have been modified to be detectable, e.g., isotopicallylabelled with ¹⁸F for use as a probe in positron emission tomography(PET) or single-photon emission computed tomography (SPECT).

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd ed., (1999) John Wiley & Sons, NY. Some of thesemasked or protected compounds are pharmaceutically acceptable; otherswill be useful as intermediates. Synthetic intermediates and processesdisclosed herein, and minor modifications thereof, are also within thescope of the invention.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyidiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates

Examples of carbonate protecting groups include methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl,allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,4-ethoxy-1-naphthyl, and methyl dithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-di nitro-4-pyridonyl.

Special—NH Protective Groups

Examples of special NH protective groups include N-Alkyl and N-ArylAmines N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN—(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-5-alkyl or —S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

Protection for the Carboxyl Group

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N-phenyl and N,N′-diisopropyl hydrazides.

C. SYNTHESIS

The compounds of the present invention may be prepared by conventionalsynthetic organic chemistry and by matrix or combinatorial methodsaccording to Schemes 1 to 11 below, and representative detailed Examples1 to 24. Those of ordinary skill in the art will be able to modify andadapt the guidance provided herein to make the disclosed compounds.

D. FORMULATION AND ADMINISTRATION

The present compounds inhibit the proteolytic activity of humancathepsin S and therefore are useful as a medicine especially in methodsfor treating patients suffering from disorders or conditions which aremodulated or regulated by the inhibition of cathepsin S activity.

The invention features a method for treating a subject with a conditionmediated by cathepsin S, said method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of the invention. The invention alsoprovides a method for inhibiting cathepsin S activity in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. A third method is a method fortreating an autoimmune disease, or inhibiting the progression of anautoimmune disease, in a subject, said method comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a disclosed compound. The autoimmune disease canbe, for example, lupus, rheumatoid arthritis, or preferably, asthma. Theinvention also provides a method for treating or inhibiting theprogression of tissue transplant rejection in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of theinvention. The administration step can occur before, during, and/orafter a tissue transplant procedure.

In view of their inhibitory effect on the proteolytic activity of humancathepsin S the compounds of the present invention may be formulatedinto various pharmaceutical forms for administration purposes. Toprepare these pharmaceutical compositions, an effective amount of aparticular compound, in base or acid addition salt form, as the activeingredient is intimately mixed with a pharmaceutically acceptablecarrier.

A carrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration or parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. These include water, glycols,oils, alcohols and the like in the case of oral liquid preparations suchas suspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. In view oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are generally employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Such additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formula(I), due to their increased water solubility over the corresponding baseform, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salt forms which thedisclosed compounds are able to form. The latter can conveniently beobtained by treating the base form with an appropriate acid. Appropriateacids comprise, for example, inorganic acids such as hydrohalic acids,e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric andthe like acids; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, palmoic and the like acids. The term addition saltalso comprises the solvates which the disclosed componds, as well as thesalts thereof, are able to form. Such solvates are for example hydrates,alcoholates and the like. Conversely the salt form can be converted bytreatment with alkali into the free base form.

Stereoisomeric form defines all the possible isomeric forms which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure. Morein particular, stereogenic centers may have the (R)- or(S)-configuration; substituents on bivalent cyclic saturated radicalsmay have either the cis- or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention.

Those of skill in the treatment of disorders or conditions mediated bythe cathepsin S enzyme could easily determine the effective daily amountfrom the test results presented hereinafter and other information. Ingeneral it is contemplated that a therapeutically effective dose wouldbe from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer thetherapeutically effective dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.05 mg to 250mg, and in particular 0.5 to 50 mg of active ingredient per unit dosageform. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mgdosage forms. Compounds of the invention may also be prepared intime-release or subcutaneous or transdermal patch formulations.Disclosed compound may also be formulated as a spray or other topical orinhalable formulations.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to thepreparation, characterization, and use of the disclosed compounds.

E. EXAMPLES Example 1

1-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneA.1-[3-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 50 g (0.35 mol) of N-acetyl-4-piperidone and 31g (0.35 mol) of morpholine in benzene (350 mL) was added a catalyticamount (˜0.25 g) of p-toluenesulfonic acid. The mixture was heated toreflux for 10 h with a Dean-Stark trap. The solvent was removed underreduced pressure to give a brown oil. The crude product was diluted withCH₂Cl₂ (175 mL) and 50.0 mL (0.35 mol) of Et₃N was added. The mixturewas cooled to 0° C. and a solution of 45.0 mL (0.35 mol) of4-chlorobenzoyl chloride in CH₂Cl₂ (50 mL) was added slowly by droppingfunnel over 1 h. The mixture was allowed to warm to room temperature andstirred overnight. The reaction was then diluted with 1 N HCl (150 mL)and stirred vigorously for 3 h. The aqueous layer was extracted withCH₂Cl₂ (3×250 mL) and the combined extracts were dried over Na₂SO₄ andthe solvent was removed under reduced pressure. The crude oil wasdiluted with EtOH (350 mL) and cooled to 0° C. To this stirred solutionwas slowly added 33.0 mL (1.06 mol) of hydrazine and the mixture wasallowed to warm to room temperature and stir overnight during which timea white precipitate formed. The volume of the reaction was reduced to˜150 mL and EtOAc (750 mL) was added to the mixture. The suspension wasstirred vigorously for 2 h and was filtered then washed with EtOAc(2×200 mL) and dried under vacuum to afford 41.4 g (42% over 3 steps) ofa pale yellow solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray), m/z calculated for C₁₄H₁₄ClN₃O [M+H]⁺276.08, observed276.0. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers): 7.65 (d,J=8.4 Hz, 2H), 7.64 (d, J=9.3 Hz, 2H), 7.58 (d, J=10.5 Hz, 2H), 7.55 (d,J=8.5 Hz, 2H), 4.94 (s, 2H), 4.78 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.90(t, J=5.8 Hz, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.36(s, 3H), 2.31 (s, 3H).

B.1-[3-(4-Chloro-phenyl)-1-(3-chloro-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Cs₂CO₃ (2.66 g, 8.2 mmol) was added to a solution of1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.0 g, 5.4 mmol) in DMF (10 mL) and stirred for 15 min.1-Bromo-3-chloropropane (1.28 g, 8.2 mmol) was added and stirred underN₂ at room temperature for 36 h. Water (50 mL) was added to the reactionand stirred for 5 min. The product precipitated out. The aqueous portionwas decanted and water was added to the residue and decanted again. Thesemisolid was taken up in CH₂Cl₂ and passed through a short plug of SiO₂(5% MeOH/EtOAc) to obtain 1.06 g (83%) of a pale yellow semisolid. MS(electrospray): exact mass calculated for C₁₇H₁₉Cl₂N₃O, 351.09; m/zfound, 352.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, a mixture of 1:1 rotamers):7.60 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H),7.36 (d, J=8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.20 (t, J=6.2 Hz,2H), 3.94 (t, J=5.8 Hz, 1H), 3.76 (t, J=5.8 Hz, 1H), 3.52 (q, J=6.1 Hz,2H), 2.84 (t, J=5.5 Hz, 1H), 2.77 (t, J=5.6 Hz, 1H), 2.37 (sextet, J=6.1Hz, 2H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).

C.1-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

1-[3-(4-Chloro-phenyl)-1-(3-chloro-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(0.053 g, 0.15 mmol) was dissolved in CH₃CN (0.5 mL) and a solution of1-(2-fluorophenyl)piperazine (0.053 g, 0.30 mmol) in CH₃CN (0.5 mL) wasadded, followed by K₂CO₃ (0.031 g, 0.22 mmol) and Bu₄Nl (0.018 g, 0.05mmol). The mixture was stirred at room temperature for 7 d. PreparativeTLC (silica, 5% MeOH/EtOAc) afforded 30 mg (41%) of the title compound.MS (electrospray): exact mass calculated for C₂₇H₃₁ClFN₅O, 495.22; m/zfound, 496.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, a mixture of 1:1 rotamers):7.60 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H),7.35 (d, J=8.3 Hz, 1H), 7.06-6.90 (m, 4H), 4.77 (s, 1H), 4.60 (s, 1H),4.10 (t, J=6.8 Hz, 2H), 3.92 (t, J=5.7 Hz, 1H), 3.74 (t, J=5.7 Hz, 1H),3.08 (br s, 4H), 2.83 (t, J=5.6 Hz, 1H), 2.77 (t, J=5.7 Hz, 1H), 2.58(br s, 4H), 2.41-2.38 (m, 2H), 2.19 (s, 1.5H), 2.13 (s, 1.5H), 2.10-2.07(m, 2H).

Example 2

1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneA.1-[3-(4-Chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 1.00 g (3.63 mmol) of1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneand 2.85 mL (36.3 mmol) of epichlorohydrin was added 1.30 g (3.99 mmol)of solid Cs₂CO₃. The reaction was stirred for 48 h and the solvent wasremoved under reduced pressure. The residue was then diluted with H₂O(50 mL) and EtOAc (50 mL). The layers were separated, and the organiclayer was washed with H₂O (25 mL) and brine (25 mL), dried over Na₂SO₄and the solvent was removed under reduced pressure. Purification byflash chromatography (silica, 0-15% acetone/CH₂Cl₂) afforded 0.72 g(60%) of a white solid. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.5. MS(electrospray): m/z calculated for C₁₇H₁₈ClN₃O₂ [M+H]⁺, 332.11, observed332.0. ¹H NMR (400 MHz, CDCl₃, a mixture of amide rotamers): 7.60 (d,J=8.6 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.36 (d,J=8.4 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, J_(ab)=15.8 Hz,2H), 4.60 (s, 2H), 4.47 (dd, J=15.3, 2.5 Hz, 1H), 4.42 (dd, J=15.0, 2.7Hz, 1H), 4.11 (dd, J=5.3, 2.5 Hz, 1H), 4.08 (dd, J=5.1, 3.3 Hz, 1H),3.99-3.85 (m, 2H), 3.73 (dt, J=5.9, 1.8 Hz, 2H), 3.37 (m, 2H), 2.87-2.80(m, 3H), 2.80-2.69 (m, 3H), 2.53 (dd, J=4.7, 2.5 Hz, 1H), 2.48 (dd,J=4.6, 2.6, 1H), 2.19 (s, 3H), 2.15 (s, 3H).

B.1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone

A solution of of1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(0.8 g, 2.42 mmol) in CH₂Cl₂ (12 mL) was treated with ytterbium(III)triflate (0.15 g, 0.24 mmol) and 1-(O-tolyl)-piperazine (0.51 g, 2.90mmol) at 25° C. The reaction mixture was stirred for 24 h and dilutedwith EtOAc (100 mL) and H₂O (50 mL). The organic layer was separated,washed with H₂O (2×50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) afforded 1.08 g (88%) of thetarget compound, a white powder. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.38. MS (electrospray): m/z 508.3 ([M+H]⁺, C₂₈H₃₄ClN₅O₂ requires507.2). ¹H NMR (CDCl₃, 400 MHz, a mixture of two rotamers): 7.60 and7.37 (AB pattern, J_(ab)=8.8 Hz, 2H), 7.54 and 7.40 (AB pattern,J_(ab)=8.8 Hz, 2H), 7.18-7.14 (m, 2H), 7.00-6.97 (m, 2H), 4.85 and 4.73(AB pattern, J_(ab)=15.5 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 2H),4.06-4.01 (m, 1H), 3.88-3.70 (m, 2H), 2.97-2.87 (m, 6H), 2.85-2.75 (m,2H), 2.65-2.55 (m, 2H), 2.51-2.48 (m, 2H), 2.29 (s, 3H), 2.21 (s, 1.5H),2.17 (s, 1.5H).

Example 3

1-{3-(4-Chloro-phenyl)-1-[2-methoxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone

A stirred solution of1-{3-(4-chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone(25 mg, 0.05 mmol) in THF (0.2 mL) was treated with NaH (1.42 mg, 0.06mmol) at 25° C. After 20 min, methyl iodide (3.7 μL, 0.06 mmol) wasadded and the reaction mixture was stirred for an additional 2 h.Preparative TLC (silica, 5% MeOH/CH₂Cl₂) afforded 14.6 mg (56%) of acolorless film. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.38. MS(electrospray): m/z 522.2 ([M+H]⁺, C₂₉H₃₆ClN₅O₂ requires 521.3). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.62 and 7.37 (AB pattern,J_(ab)=8.8 Hz, 2H), 7.55 and 7.40 (AB pattern, J_(ab)=8.8 Hz, 2H),7.18-7.14 (m, 2H), 7.02-6.95 (m, 2H), 4.82 and 4.75 (AB pattern,J_(ab)=15.5 Hz, 1H), 4.62 (s, 1H), 4.30-4.25 (m, 1H), 4.09-3.73 (m, 4H),3.29 (s, 1.5H), 3.27 (s, 1.5H), 2.93-2.55 (m, 12H), 2.30 (s, 3H), 2.21(s, 1.5H), 2.16 (s, 1.5H).

Example 4

1-[1-{2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA.1-[3-(4-Iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A flask equipped with a Dean-Stark trap was charged withN-acetyl-4-piperidone (27.29 g, 137 mmol), piperidine (16.5 mL, 129mmol), p-toluene-sulfonic acid (0.5 g) and benzene (150 mL). The mixturewas heated to 125° C. After 8 h the mixture was allowed to cool, andconcentrated in vacuo to give the corresponding enamine (35 g). Asolution of p-iodobenzoyl chloride (9.28 g, 34.8 mmol) in CH₂Cl₂ (40 mL)was added dropwise to a 0° C. solution of the enamine (11.0 g, ca. 41mmol) in CH₂Cl₂ (80 mL) over 2 h. The mixture was then allowed to warmto room temperature and stirred for an additional 17 h. The solution wastreated with 1 N HCl (200 mL) and stirred vigorously for 5 h. The layerswere separated and the aqueous layer was extracted with CH₂Cl₂ (3×150mL). The combined extracts were dried over Na₂SO₄ and concentrated. Theresidue was dissolved in EtOH (200 mL) and treated with NH₂NH₂ (16.0 mL,51 mmol). The mixture was stirred for 17 h and H₂O (300 mL) was added.The precipitate formed was collected by filtration and air dried to give8.82 g (59%) of1-[3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanonewhich was suitable for use without further purification. TLC (silica, 5%MeOH/CH₂Cl₂): R_(f)=0.3. MS (electrospray): m/z calculated forC₁₄H₁₅lN₃O [M+H]⁺368.03, found 368.0. ¹H NMR (CD₃OD/CDCl₃, 500 MHz, amixture of amide rotamers): 7.72 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.3 Hz,2H), 7.24 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 4.69 (s, 2H), 4.56(s, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.79, (t, J=5.7Hz, 2H), 2.72, (t, J=5.8 Hz, 2H), 2.13 (s, 3H), 2.08 (s, 3H).

B.1-[3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Cs₂CO₃ (1.30 g, 4.01 mmol) was added to a solution of1-[3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.34 g, 3.65 mmol) and epichlorohydrin (2.85 mL, 36.4 mmol) in DMF(10.0 mL). The mixture was stirred for 17 h then partitioned betweenEtOAc (400 mL) and saturated NaHCO₃ (150 mL). The NaHCO₃ layer wasextracted with EtOAc (2×150 mL). The combined extracts were washed withH₂O (2×150 mL), brine (150 mL), dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography (silica, 10-25%acetone/CH₂Cl₂) to give 890 mg (58%) of the title compound. HPLC,t_(R)=5.53 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna2.1×150 mm column, 60% MeOH/H₂O (0.5% AcOH) to 90% MeOH/H₂O (0.5% AcOH),held at initial conditions for 2 min then ramped to final conditionsover 5 min.) MS (electrospray), m/z calculated for C₁₇H₁₈lN₃O₂Na[M+Na]⁺445.04, found 445.95. ¹H NMR (CDCl₃, 500 MHz, a mixture of amiderotamers): 7.76 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.42 (d,J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.80 and 4.73 (A and B of ABquartet, J_(ab)=15.6 Hz, 2H), 4.60 (s, 2H), 4.84 (dd, J=15.1, 2.1 Hz,1H), 4.42 (dd, J=15.0, 2.1 Hz, 1H), 4.11 (t, J=5.0, Hz, 1H), 4.08 (t,J=5.0 Hz, 1H), 3.98-3.87 (m, 2H), 3.74 (m, 2H), 3.34 (m, 2H), 2.87-2.72(m, 6H), 2.52 (dd, J=4.6, 2.6 Hz, 1H), 2.48 (dd, J=4.5, 2.6, 1H), 2.20(s, 3H), 2.14 (s, 3H).

C.1-[1-[2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

1-[3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(62 mg, 0.15 mmol) and 4-(2-hydroxyphenyl)-piperazine (34 mg, 0.19 mmol)were combined in CH₂Cl₂ (0.5 mL) and the solution treated withYb(OTf)₃.H₂O (44 mg, 0.071 mmol). The mixture was shaken for 72 h thendiluted with CH₂Cl₂ (1 mL). Purification by preparative TLC (silica, 10%MeOH/CH₂Cl₂) gave 45 mg (51%) of an off-white powder. TLC (silica, 8%MeOH/CH₂Cl₂): R_(f)=0.2. MS (electrospray): m/z calculated forC₂₇H₃₃lN₅O₃ [M+H]⁺602.15, found 602.2. ¹H NMR (CDCl₃, 500 MHz, a mixtureof amide rotamers): 7.76 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.42(d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.14 (m, 1H), 7.80 (t, J=7.7Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.7 Hz, 1H), 4.83 and 4.72(A and B of AB quartet, J_(ab)=15.6 Hz, 1H), 4.61 (s, 1H), 4.22-4.15 (m,2H), 4.02 (m, 2H), 3.88 (m, 1H), 3.76 (m, 3H), 3.00-2.49 (m, 11H), 2.20(s, 1.5H), 2.15 (s, 1.5H).

Example 5

1-[1-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA.1-[3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of N-acetyl-4-piperidone (2.82 g, 20 mmol), morpholine (1.93mL, 22 mmol) and p-toluenesulfonic acid (5 mg) in benzene (8.5 mL) wasrefluxed for 8 h in a Dean-Stark apparatus. The solvent was removed andthe residue dissolved in CH₂Cl₂ (20 mL). Triethylamine (3.1 mL) wasadded and p-trifluoromethylbenzoyl chloride (3.27 mL, 22 mmol) in CH₂Cl₂(4 mL) was added dropwise into the solution at 0° C. The reactionmixture was stirred at 25° C. for 24 h and diluted with aqueous HCl (5%,25 mL). After stirring for another 30 min, the organic layer wasseparated, washed with H₂O (20 mL), dried (Na₂SO₄), and concentrated.The residue was dissolved in EtOH (95%, 18 mL) and treated at 0° C. withhydrazine (2.9 mL, 60 mmol). The mixture was stirred at 25° C. for 3 hand H₂O (4 mL) was added. Most of the volatiles were removed and theresidue extracted with CH₂Cl₂ (50 mL). The organic layer was separated,washed with H₂O (20 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) provided 5.1 g (83%) of a whitepowder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.30. MS (electrospray):m/z 332.0 ([M+Na]⁺, C₁₅H₁₄F₃N₃O requires 309.1). ¹H NMR (CDCl₃, 400 MHz,a mixture of two rotamers): 7.73-7.67 (m, 4H), 4.85 (s, 1.2H), 4.68 (s,0.8H), 3.96 (t, J=4.5 Hz, 0.8H), 3.78 (t, J=4.5 Hz, 1.2H), 2.89 (t,J=4.5 Hz, 1.2H), 2.83 (t, J=4.5 Hz, 0.8H), 2.23 (s, 1.8H), 2.18 (s,1.2H).

B.1-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of1-[3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(2.4 g, 7.77 mmol) in DMF (15 mL) was treated with cesium carbonate(5.05 g, 15.5 mmol) and epichlorohydrin (6.1 mL, 77.7 mmol) at 25° C.and stirred for 24 h before it was diluted with EtOAc (100 mL) and H₂O(50 mL). The organic layer was separated, washed with H₂O (2×50 mL),brine (50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 10% acetone/CH₂Cl₂) provided 2.30 g (81%) of awhite powder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.35. MS(electrospray): m/z 388.0 ([M+Na]⁺, C₁₈H₁₈F₃N₃O₂ requires 365.1). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.77 and 7.63 (AB pattern,J_(ab)=8.2 Hz, 2H), 7.71 and 7.67 (AB pattern, J_(ab)=8.4 Hz, 2H), 4.82and 4.76 (AB pattern, J_(ab)=15.5 Hz, 1.2H), 4.58 (s, 0.8H), 4.45-4.35(m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30(m, 1H), 2.80-2.67 (m, 3H), 2.48-2.42 (m, 1H), 2.13 (s, 1.3H), 2.08 (s,1.7H).

C.1-[1-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl-ethanone

A solution of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.16 g, 3.20 mmol) in CH₂Cl₂ (15 mL) was treated with ytterbium(III)triflate (0.40 g, 0.64 mmol) and 1-(O-tolyl)-piperazine (0.84 g, 4.77mmol) at 25° C. and stirred for 48 h before it was diluted with CH₂Cl₂(100 mL) and H₂O (50 mL). The organic layer was separated, washed withH₂O (2×50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) afforded 1.54 g (89%) of a whitepowder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.35. MS (electrospray):m/z 542.3 ([M+H]⁺, C₂₉H₃₄F₃N₅O₂ requires 541.3). ¹H NMR (CDCl₃, 400 MHz,a mixture of two rotamers): 7.82 and 7.65 (AB pattern, J_(ab)=8.2 Hz,2H), 7.72 and 7.68 (AB pattern, J_(ab)=8.4 Hz, 2H), 7.18-6.97 (m, 4H),4.88 and 4.76 (AB pattern, J_(ab)=16 Hz, 0.9H), 4.65 (s, 1.1H),4.23-4.12 (m, 2H), 4.08-4.00 (m, 2H), 3.88-3.70 (m, 2H), 3.02-2.85 (m,6H), 2.85-2.75 (m, 2H), 2.65-2.55 (m, 2H), 2.53-2.45 (m, 2H), 2.29 (s,3H), 2.21 (s, 1.8H), 2.17 (s, 1.2H).

Example 6

2-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile

A solution of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(0.84 g, 2.30 mmol) in CH₂Cl₂ (10 mL) was treated with ytterbium(III)triflate (0.29 g, 0.46 mmol) and 1-(2-cyanophenyl)-piperazine (0.75 g,3.5 mmol) at 25° C. and stirred for 48 h before it was diluted withCH₂Cl₂ (100 mL) and H₂O (50 mL). The organic layer was separated, washedwith H₂O (2×50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 5% MeOH/CH₂Cl₂) afforded 1.15 g (90%) of lightyellow crystals. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.30. MS(electrospray): m/z 553.3 ([M+H]⁺, C₂₉H₃₁F₃N₆O₂ requires 552.3). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.82 and 7.68 (AB pattern,J_(ab)=8.2 Hz, 2H), 7.76 and 7.72 (AB pattern, J_(ab)=8.4 Hz, 2H),7.60-7.48 (m, 2H), 7.05-7.00 (m, 2H), 4.90 and 4.78 (AB pattern,J_(ab)=16 Hz, 1H), 4.69 (s, 1H), 4.30-3.71 (m, 6H), 3.25 (m, 4H),3.02-2.75 (m, 4H), 2.70-2.65 (m, 2H), 2.60-2.53 (m, 2H), 2.23 (s, 1.5H),2.18 (s, 1.5H).

Example 7

1-[3-(3,4-Dichloro-phenyl)-pyrazol-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olA. 3-(3,4-Dichloro-phenyl)-1-oxiranylmethyl-1H-pyrazole

A stirred solution of 3-(3,4-dichlorophenyl)pyrazole (300 mg, 1.4 mmol)in DMF (5 mL) was treated with cesium carbonate (550 mg, 1.69 mmol) andepichlorohydrin (1.1 mL, 14.0 mmol) at room temperature for 18 h. Thecrude reaction mixture was then partitioned between EtOAc (50 mL) andwater (35 mL). The aqueous phase was further extracted (2×50 mL) and thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure to yield crude product.Purification by column chromatography (silica, 25% EtOAc/hexanes)afforded 308 mg (82%) of the title compound. ¹NMR (400 MHz, CDCl₃): 7.83(d, J=2 Hz, 1H), 7.54 (dd, J=2, 8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.38(d, J=8 Hz, 1H), 6.48 (d, J=2 Hz, 1H), 4.45 (dd, J=3, 9.7 Hz, 1H), 4.12(dd, J=6, 15 Hz, 1H), 3.31 (m, 1H), 2.81 (dd, J=4.0, 4.6 Hz, 1H), 2.47(dd, J=2.6, 4.7 Hz, 1H).

B.1-[3-(3,4-Dichloro-phenyl)-pyrazol-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-ol

A solution of 3-(3,4-dichloro-phenyl)-1-oxiranylmethyl-1H-pyrazole (30mg, 0.11 mmol) and 1-(2-methylphenyl)-piperazine (22 mg, 0.12 mmol) inEtOH (1 mL) was heated to 80° C. overnight. Removal of solvent andpurification by column chromatography (silica, 0-5% acetone/CH₂Cl₂)afforded 35 mg (70%) of the title compound. ¹H NMR (400 MHz, CDCl₃):7.89 (d, J=2 Hz, 1H), 7.61 (dd, J=2, 8.7 Hz, 1H), 7.57 (d, J=2 Hz, 1H),7.45 (d, J=8.4 Hz, 1H), 7.16 (m, 2H), 6.99 (m, 2H), 6.54 (d, J=2.3 Hz,1H), 4.31 (m, 1H), 4.18 (m, 2H), 2.93 (m, 4H), 2.60 (m, 2H), 2.47 (m,3H), 2.88 (s, 3H).

Example 8

1-[1-[2-(2-Piperazin-1-yl-ethylamino)-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA.1-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-yl)-propan-2-one

A solution of DMSO (3.55 mL, 50 mmol) in CH₂Cl₂ (7 mL) was treated withoxalyl chloride (2.90 mL, 33 mmol) at −78° C. and stirred for 30 min. Asolution of1-[1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(1.8 g, 3.3 mmol) in CH₂Cl₂ (7 mL) was then slowly added and thereaction mixture was stirred for an additional 30 min before it wasquenched with addition of triethylamine (18.4 mL, 132 mmol). Thereaction mixture was slowly warmed to 25° C. and diluted with EtOAc (50mL) and sat. NaHCO₃ (30 mL). The organic layer was separated, washedwith H₂O (2×50 mL), dried over Na₂SO₄, and concentrated. Columnchromatography (silica, 2-5% MeOH/CH₂Cl₂) afforded 1.50 g (83%) of alight yellow powder. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.35. MS(electrospray): m/z 540.3 ([M+H]⁺, C₂₉H₃₂F₃N₅O₂ requires 539.3). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.78 and 7.62 (AB pattern,J_(ab)=8.2 Hz, 2H), 7.70 and 7.64 (AB pattern, J_(ab)=8.4 Hz, 2H),7.18-6.95 (m, 4H), 5.10 (s, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.68 (s,1H), 3.96 (t, J=4.4 Hz, 1H), 3.78 (t, J=4.4 Hz, 1H), 3.47 (3.47 (s, 4H),3.34 (s, 2H), 2.74-2.65 (m, 6H), 2.29 (s, 3H), 2.20 (s, 1.5H), 2.17 (s,1.5H).

B.1-1-[2-(2-piperazin-1-yl-ethylamino)-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of1-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-one(54 mg, 0.1 mmol) in 1,2-dichloroethane (0.5 mL) was treated with1-(2-aminoethyl)piperazine (26 μL, 0.2 mmol) and glacial acetic acid (34μL, 0.6 mmol) at 25° C. and stirred for 30 min. Sodiumtriacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the reactionmixture was stirred for an additional 4 h before it was quenched withCH₂Cl₂ (5 mL) and sat. NaHCO₃ (5 mL). The organic layer was separated,washed with H₂O (2×5 mL), dried over Na₂SO₄, and concentrated.Preparative TLC (silica, 10% MeOH/CH₂Cl₂) afforded 22 mg (35%) of alight yellow film. TLC (10% MeOH/CH₂Cl₂): R_(f)=0.2. MS (electrospray):m/z 653.3 ([M+H]⁺, C₃₅H₄₇F₃N₈O requires 652.4). ¹H NMR (CDCl₃, 400 MHz,a mixture of two rotamers): 7.78-7.60 (m, 4H), 7.18-6.82 (m, 4H),4.88-4.30 (m, 2H), 4.23-3.90 (m, 2H), 3.85-3.70 (m, 2H), 3.22-2.85 (m,10H), 2.85-2.30 (m, 15H), 2.30 (s, 3H), 2.21 (s, 1.5H), 2.17 (s, 1.5H).

Example 9

1-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester A.3-(4-Iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

p-Toluenesulfonic acid (0.055 g. 0.29 mmol) and morpholine (4.76 mL, 54mmol) were added to a solution of tert-butyl4-oxo-1-piperidinecarboxylate (10.3 g. 52 mmol) in benzene (22 mL). Thereaction mixture was heated in a flask equipped with a condenser and aDean-Stark trap at reflux for 20 h. The reaction mixture was cooled andconcentrated in vacuo to give the enamine which was used without furtherpurification. The enamine was dissolved in CH₂Cl₂ (60 mL) and cooled to0° C. Triethylamine (8.67 mL, 62 mmol) was added, followed by dropwiseaddition of 4-iodobenzoyl chloride (13.8 g, 52 mmol) dissolved in CH₂Cl₂(10 mL). The reaction mixture was allowed to warm to room temperatureand stirred for 72 h. The reaction mixture was poured over water (200mL) and the CH₂Cl₂ layer was separated, dried (Na₂SO₄), andconcentrated. The resulting oil was taken up in EtOH (200 mL) andtreated with hydrazine (4.88 mL, 155 mmol) at 0° C. The reaction mixturewas allowed to warm to room temperature and stirred for 17 h. Themixture was concentrated and the resulting material was triturated withEtOAc to afford 9.52 g (43%) of a white solid. TLC (silica, 10%acetone/CH₂Cl₂): R_(f)=0.18. MS (electrospray): m/z 426.0 (426.1calculated for C₁₇H₂₀lN₃O₂, [M+H]⁺). ¹H NMR (400 MHz, CDCl₃): 7.74 (brs, 2H), 7.31 (br d, J=8.0 Hz, 2H), 4.63 (br s, 2H), 3.73 (br s, 2H),2.77 (br s, 2H), 1.49 (s, 9H).

B.3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

Cesium carbonate (1.84 g, 5.65 mmol) was added to a solution ofepichlorohydrin (3.68 mL, 47.05 mmol) and3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (2.0 g, 4.71 mmol) in DMF (10 mL). The reactionmixture was allowed to stir for 24 h, then partitioned between aqueousNaHCO₃ and EtOAc. The aqueous layer was extracted with EtOAc and thecombined organic layers were washed with water and brine, dried(Na₂SO₄), and concentrated. Purification by column chromatography(silica, 0-10% acetone/CH₂Cl₂) afforded 2.26 g (69%) of a white foam.TLC (silica, 10% acetone/CH₂Cl₂): R_(f)=0.44. MS (electrospray): m/z482.0 (482.1 calculated for C₂₀H₂₄lN₃O₃, [M+H]⁺). ¹H NMR (400 MHz,CDCl₃): 7.60 (br s, 2H), 7.28 (br d, J=8.2 Hz, 2H), 4.48 (br s, 2H),4.32 (br d, J=14.8 Hz, 1H), 3.99 (dd, J=15.0, 5.4 Hz, 1H), 3.61 (br s,1H), 3.26-3.20 (m, 1H), 2.72 (t, J=4.4 Hz, 1H), 2.65-2.58 (m, 2H), 2.40(br s, 1H), 1.36 (s, 9H).

C.1-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

Ytterbium (III) trifluoromethanesulfonate hydrate (0.193 g, 0.311 mmol)and 1-(2-cyanophenyl)-piperazine (0.292 g, 1.56 mmol) were dissolved inCH₂Cl₂ (2 mL) and added to a solution of3-(4-iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester in CH₂Cl₂ (5 mL). The reaction mixture was allowedto stir for 48 h at 25° C. Purification by flash chromatography (silica,0-15% acetone/CH₂Cl₂) afforded 392 mg (56%) of a white foam. TLC(silica, 10% acetone/CH₂Cl₂): R_(f)=0.41. MS (electrospray): m/z 669.2(669.2 calculated for C₃₁H₃₇lN₆O₃, [M+H]⁺). ¹H NMR (400 MHz, CDCl₃):7.73 (br s, 2H), 7.58-7.56 (m, 1H), 7.52-7.48 (m, 1H)_(i) 7.39 (br d,J=7.1 Hz, 2H), 7.04-7.00 (m, 2H), 4.60 (br s, 2H), 4.06-4.04 (m, 2H),4.06-4.04 (m, 1H), 3.76-3.70 (m, 2H), 3.26 (br s, 4H), 2.84-2.38 (m,7H), 1.56-1.53 (m, 2H), 1.48 (s, 9H).

Example 10

1-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide A.2-(4-{2-Hydroxy-3-[3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrile

Trifluoroacetic acid (3 mL) was added to a solution of1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (0.402 g, 0.601 mmol) in CH₂Cl₂ (3 mL) and thereaction mixture was stirred for 2 h. The mixture was concentrated, thendiluted with EtOAc. The organic layer was washed with aqueous NaHCO₃ andbrine, dried (Na₂SO₄), and concentrated to afford the amine (0.342 g,100%) as a yellowish foam. TLC (silica, 10% acetone/CH₂Cl₂): R_(f)=0.14.MS (electrospray): m/z 569.2 (569.1, calculated for C₂₆H₂₉lN₆O, [M+H]⁺).¹H NMR (400 MHz, CDCl₃:CD₃OD(6:1)): 7.73 (d, J=8.6 Hz, 2H), 7.56 (dd,J=7.6, 1.8 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.09(t, J=7.6 Hz, 1H), 7.02 (dd, J=8.4 Hz, 1H), 4.43-4.36 (m, 1H), 4.31 (s,2H), 4.21 (dd, J=14.1, 4.5 Hz, 1H), 4.11 (dd, J=14.5, 6.3 Hz, 1H),3.54-3.49 (m, 2H), 3.40-3.24 (m, 8H), 3.18-3.06 (m, 3H), 3.03-2.95 (m,3H).

B.1-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide

Diisopropylethylamine (0.531 mL, 3.05 mmol), DMAP (5 mg), andtrimethylsilyl isocyanate (0.413 mL, 3.05 mmol) were added to a solutionof2-(4-{2-hydroxy-3-[3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrilein pyridine (3 mL) and CH₂Cl₂(6 mL). The reaction mixture was stirredfor 20 h, then partitioned between aqueous NaHCO₃ and CH₂Cl₂. The CH₂Cl₂layer was washed with brine, dried (Na₂SO₄), and concentrated. Theresulting product was dissolved in CH₂Cl₂ (5 mL) and treated with 21 wt% sodium ethoxide in EtOH (0.5 mL) for 3 h. The reaction mixture waswashed with brine, dried (Na₂SO₄), and concentrated. Purification bycolumn chromatography (silica, 0-10% MeOH/CH₂Cl₂) afforded 290 mg (78%)of the title compound. HPLC (reverse phase conditions), t_(R)=4.21 min.MS (electrospray): m/z 612.2 (612.5, calculated for C₂₇H₃₀lN₇O₂, M⁺+H).¹H NMR (400 MHz, CDCl₃): 7.73 (d, J=8.6 Hz, 2H), 7.57 (dd, J=7.6, 1.6Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.05 (t, J=7.6Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.64 (br s, 2H), 4.57 (br s, 2H), 4.30(br s, 1H), 4.20 (dd, J=14.1, 3.3 Hz, 1H), 4.06 (dd, J=14.1, 6.3 Hz,1H), 3.82-3.65 (m, 2H), 3.29-3.20 (m, 4H), 3.04-2.80 (m, 6H), 2.68 (brs, 2H).

Example 11

Carbamic acid1-[5-carbamoyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-[4-(2-cyano-phenyl)-piperazin-1-yl]-ethylester

The title compound (13 mg, 3%) was obtained along with1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid as described in example 10. MS (electrospray): m/z 655.2 (655.2,calculated for C₂₈H₃₁lN₈O₃, [M+H]⁺). HPLC (reverse phase conditions):t_(R)=6.29 min. ¹H NMR (400 MHz, CDCl₃): 7.69 (d, J=8.1 Hz, 2H), 7.50(d, J=7.52, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 2H), 6.96(t, J=9.0 Hz, 2H), 4.64 (br s, 2H), 4.08 (d, J=16.8 Hz, 2H), 3.96 (dd,J=14.0, 6.6 Hz, 1H), 3.80-3.69 (m, 2H), 3.10-2.80 (m, 4H), 2.66 (br s,2H), 2.50 (br s, 2H).

Example 12

1-{3-(3-Amino-4-chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneA.1-[3-(4-Chloro-3-nitro-Phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A flask equipped with a Dean-Stark trap was charged withN-acetyl-4-piperidone (27.29 g, 137 mmol), piperidine (16.5 mL, 129mmol), p-toluene-sulfonic acid (0.5 g) and benzene (150 mL). The mixturewas heated to 125° C. After 8 h the mixture was allowed to cool, andconcentrated in vacuo to give the corresponding enamine (35 g). Asolution of the enamine (3.87 g, 20.0 mmol) in dichloromethane (24 mL)was treated with triethylamine (3.07 mL, 22.0 mmol) and4-chloro-3-nitrobenzoyl chloride (4.84 g, 22.0 mmol). The reactionmixture was stirred at 0° C. for 1 h and then at room temperature for 16h. Hydrazine (1.88 mL, 60 mmol) was added to the reaction mixture. Thissolution was stirred at room temperature for an additional 16 h. Thesolvents were removed under reduced pressure. Ethyl acetate (100 mL) wasadded to the residue to form a suspension. This suspension was filteredand dried to afford 6.4 g (100%) of a yellow solid. MS (electrospray):m/z 321.0 (321.0, calculated for C₁₄H₁₃ClN₄O₃, [M+H]⁺). ¹H NMR (CDCl₃,400 MHz, a mixture of two rotamers): 8.10-8.00 (m, 3H), 4.90 (s, 0.8H),4.85 (s, 1.2H), 3.96 (m, 2H), 2.95 (m, 2H), 2.20 (s, 3H).

B. 1-[3-(4-Chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of1-[3-(4-chloro-3-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(6.4 g, 20.0 mmol) in DMF (60 mL) was treated with cesium carbonate(13.0 g, 40 mmol) and epichlorohydrin (15.6 mL, 200.0 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for anadditional 24 h before it was diluted with ethyl acetate (350 mL) andwater (50 mL). The organic layer was separated, washed with water (2×50mL), brine (50 mL), dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by column chromatography(silica, 10% acetone/CH₂Cl₂) to provide 7.5 g (83%) of a light yellowpowder. MS (electrospray): m/z 377.0 (377.0, calculated forC₁₇H₁₇ClN₄O₄, [M+H]⁺). ¹H NMR (CDCl₃, 400 MHz, a mixture of tworotamers): 8.15-8.05 (m, 1H), 7.75-7.65 (m, 1H), 7.55-7.45 (m, 1H),4.80-4.65 (m, 1.2H), 4.60 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m,1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2.67(m, 3H), 2.55-2.48 (m, 1H), 2.15 (s, 1.7H), 2.10 (s, 1.3H).

C.1-{3-(4-Chloro-3-nitro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone

A solution of1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated withytterbium(III) triflate (0.25 g, 0.40 mmol) and1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature.The reaction mixture was stirred at room temperature for 16 h anddiluted with dichloromethane (100 mL) and water (50 mL). The organiclayer was separated, washed with water (2×50 mL), dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, 5% MeOH/CH₂Cl₂) to afford0.98 g (90%) of the desired product as a light yellow solid. MS(electrospray): m/z 553.2 (553.2, calculated for C₂₈H₃₃ClN₆O₄, [M+H]⁺).¹H NMR (CDCl₃, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H),7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10 (m, 2H), 7.05-6.95 (m,2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m,4H), 3.00-2.40 (m, 12H), 2.20 (s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).

D.1-{3-(3-amino-4-chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone

To a solution of sodium hydrosulfite (1.28 g, 7.3 mmol) in 30 mL waterwas added1-{3-(4-chloro-3-nitro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone(810 mg, 1.5 mmol) in 15 mL THF. The reaction mixture was stirred atroom temperature for 5 min. The color of the solution changed from lightyellow to colorless. Hydrochloride solution (1 N, 10 mL) was added tothe reaction mixture. This solution was stirred at room temperature for30 min, and treated with saturated sodium bicarbonate until the pH ofthe solution between 7 to 8. The product was extracted withdichloromethane (3×80 mL). The organic phases were combined, dried oversodium sulfate, and concentrated under reduced pressure to a residue.This residue was purified by column chromatography (silica, 5-20%MeOH/CH₂Cl₂) to afford 644 mg (84.1%) of the title compound. MS(electrospray): m/z 523.3 (523.3, calculated for C₂₈H₃₅ClN₆O₂, [M+H]⁺).¹H NMR (CDCl₃, 400 MHz, a mixture of two rotamers): 7.30-6.70 (m, 7H),4.80-4.60 (m, 1H), 4.55 (s, 1H), 4.20-4.05 (m, 4H), 3.95-3.90 (m, 2H),3.80-3.60 (m, 2H), 2.90-2.30 (m, 9H), 2.20 (s, 3H), 2.15 (s, 1.5H), 2.10(s, 1.5H).

Example 13

(R)-1-(3-(4-Bromo-phenyl)-1-{3-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneA. (2S)-1-tert-Butyldimethylsilylglycidol

tert-Butylchlorodimethylsilane (9.41 g, 62.4 mmol) followed by Et₃N(13.5 mL, 96.8 mmol) was added to a 0° C. solution of R-(+)-glycidol(3.88 g, 52.4 mmol) in CH₂Cl₂ (100 mL). The solution was allowed to warmto 23° C. with stirring over 17 h. The resulting pink solution wasdiluted with Et₂O (250 mL) and stirred an additional 30 min. Thesolution was partitioned between Et₂O (800 mL) and sat. aqueous NaHCO₃(200 mL). The Et₂O layer was washed with sat. aqueous NaHCO₃ (250 mL),H₂O (3×200 mL), brine (100 mL), dried over Na₂SO₄ and concentrated.Purification of the residue by column chromatography (silica, 5-10%Et₂O/hexanes) provided 8.21 g (84%) of the title compound. TLC (silica,10% Et₂O/hexanes): R_(f) 0.5. ¹H NMR (CDCl₃, 400 MHz): 3.85 (dd, J=11.9,3.2 Hz, 1H), 3.66 (dd, J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H), 2.77 (dd,J=5.0, 4.2 Hz, 1H), 2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s,3H), 0.07 (s, 3H).

B.1-[3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A flask equipped with a Dean-Stark trap was charged withN-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 mL, 779 mmol),pTsOH (3.7 g) and benzene (500 mL). The mixture was heated to 125° C.After 17 h the mixture was allowed to cool and divided into twoportions. A solution of p-bromobenzoyl chloride (70.0 g, 319 mmol) inCH₂Cl₂ (400 mL) was added dropwise to a 0° C. solution of the enamine(ca. 355 mmol) in CH₂Cl₂ (320 mL) over 15 h. The mixture was thenallowed to warm to 23° C. and stirred for an additional 5 h. Thesolution was treated with 1 N HCl (500 mL) and stirred vigorously for1.5 h. The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (2×300 mL). The combined extracts were washed with sat.aqueous NaHCO₃ (300 mL), H₂O (300 mL), brine (300 mL), dried over Na₂SO₄and concentrated. The residue was dissolved in MeOH (300 mL) and treatedwith NH₂NH₂ (50.0 mL, 1.59 mol). The mixture was stirred for 17 h beforethe precipitate formed was collected by filtration and air dried to give52 g (50%) of the title compound which was suitable for use withoutfurther purification. TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): m/z calculated for C₁₄H₁₅ ⁷⁹BrN₃O [M+H]⁺, 320.04, found320. ¹H NMR (CD₃OD/CDCl₃, 400 MHz, a mixture of amide rotamers): 7.53and 7.35 (A and B of AA′BB′, J=8.5 Hz, 2H), 7.51 and 7.39 (A and B ofAA′BB′, J=8.6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J=5.9 Hz,2H), 3.71 (t, J=5.8 Hz, 2H), 2.81, (t, J=5.8 Hz, 2H), 2.74, (t, J=5.8Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).

C.(S)-1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of KHMDS in toluene (0.5 M, 3.7 mL, 1.85 mmol) was added to a0° C. solution of1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(492 mg, 1.54 mmol) in DMF (4.0 mL). The mixture was stirred for 1 hbefore (2S)-1-tert-butyldimethylsilylglycidol (870 mg, 4.62 mmol) wasadded neat via syringe. The mixture was stirred an additional 48 h andpartitioned between EtOAc (300 mL) and sat. aqueous NaHCO₃ (100 mL). Theaqueous layer was extracted with EtOAc (2×100 mL). The combined extractswere washed with H₂O (2×100 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated. The residue was dissolved in MeOH (50 mL) and treated withCSA (97 mg). The mixture was stirred for 17 h and concentrated todryness. The residue was suspended in MeC(OMe)₃ (50 mL) and stirred foran additional 17 h. The mixture was diluted with EtOAc (400 mL) andwashed with saturated aqueous NaHCO₃ (50 mL), H₂O (2×50 mL), brine (50mL), dried over Na₂SO₄ and concentrated. The crude orthoester wasdissolved in CH₂Cl₂ (5 mL), cooled to 0° C., and treated with AcBr (0.18mL, 2.4 mmol). The mixture was allowed to warm with stirring over 4 hbefore being worked up as described above. The crude acetyl-bromideobtained was dissolved in MeOH (50 mL), treated with K₂CO₃ (207 mg, 1.50mmol) and stirred for 4 h. The reaction mixture was diluted with EtOAc(400 mL) and washed with saturated aqueous NH₄Cl (100 mL). The EtOAclayer was washed with H₂O (2×100 mL), brine (100 mL), dried over Na₂SO₄and concentrated. The crude product was purified by columnchromatography (silica, 10-40% acetone/CH₂Cl₂) to afford 158 mg (27%) ofthe title compound. Chiral HPLC (Daicel OD, 0.5% Et₂NH/MeOH) analysisindicated >95% optical purity. HPLC (reverse phase conditions):t_(R)=4.90 min. MS (electrospray): m/z calculated for C₁₇H₁₉ ⁷⁹BrN₃O₂[M⁺+H], 376.07, found 376.0. ¹H NMR (CDCl₃, 400 MHz, a mixture of amiderotamers): 7.47 (d with fine splittings (partially obscured), J=8.5, Hz,2H), 7.44 (m, 4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71and 4.64 (A and B of AB quartet, J_(ab)=15.7 Hz, 2H), 4.51 (s, 2H), 4.39(dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd,J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m,2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H),2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).

D.(R)-1-(3-(4-Bromo-phenyl)-1-{3-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone

(S)-1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(37 mg, 0.98 mmol) and 4-(2-methyl-5-chlorophenyl)piperazine (36 mg,0.17 mmol) were combined in EtOH (0.4 mL) and heated to 70° C. After 18h the mixture Was allowed to cool, diluted with CH₂Cl₂ and purified bypreparative TLC (silica, 8% MeOH/CH₂Cl₂) to give 35 mg (61%) the titlecompound. HPLC (reverse phase conditions): t_(R)=4.41 min. MS(electrospray): m/z calculated for C₂₈H₃₄ ³⁵Cl⁷⁹BrN₅O₂ [M⁺+H], 586.16,found 586.2. ¹H NMR (CDCl₃, 400 MHz, a mixture of amide rotamers): 7.56(d (partially obscured), J=8.5, Hz, 2H), 7.53 (s, 4H), 7.48 (d, J=8.5Hz, 2H), 7.08 (br d, J=8.5 Hz, 1H), 6.95 (m, 2H), 4.85 and 4.73 (A and Bof AB quartet, J_(ab)=15.6 Hz, 1H), 4.62 (s, 1H), 4.20 (m, 2H), 4.04 (m,2H), 3.90-3.71 (m, 2H), 2.92-2.53 (m, 11H), 2.21 (s, 1.5H), 2.16 (s,1.5H).

Example 14

2-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-fluoro-propyl}-piperazin-1-yl)-benzonitrile

A solution of2-(4-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile(150 mg, 0.27 mmol) in CH₂Cl₂ (1 mL) was treated with DAST (Et₂NSF₃, 7μL, 0.60 mmol) at −78° C. The reaction mixture was slowly warmed to 25°C. for 1 h and then to 60° C. for an additional 2 h. Preparative TLC(silica, 5% MeOH/CH₂Cl₂) provided 75 mg (50%) of the title compound as alight yellow powder. TLC (5% MeOH/CH₂Cl₂): R_(f)=0.28. MS(electrospray): m/z 555.2 ([M+H]⁺, C₂₉H₃₀F₄N₆O requires 554.2). ¹H NMR(CDCl₃, 400 MHz, a mixture of two rotamers): 7.71 and 7.59 (AB pattern,J_(ab)=8.2 Hz, 2H), 7.66 and 7.62 (AB pattern, J_(ab)=8.4 Hz, 2H),7.50-7.38 (m, 2H), 6.96-6.92 (m, 2H), 5.01 (dp, J=49.0, 3.0 Hz, 1H),4.77 and 4.73 (AB pattern, J_(ab)=15.7 Hz, 1.1H), 4.59 (s, 0.9H),4.41-4.18 (m, 2H), 3.95-3.80 (m, 1H), 3.69 (dd, J=5.5, 5.5 Hz, 1H), 3.18(m, 4H), 2.83-2.65 (m, 8H), 2.14 (s, 1.6H), 2.10 (s, 1.4H).

Example 15

(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-aceticacid methyl ester A. 4-Chloro-3-methyl-benzoyl chloride

To a suspension of 52.55 g (0.31 mol) of 4-chloro-3-methyl-benzoic acidin CH₂Cl₂ (1.2 L) with DMF (1 mL) at 0° C. under N₂ with an outletsparging through 2.5 N sodium hydroxide was added 29.56 mL (0.339 mol)of oxalyl chloride. The mixture was allowed to warm to room temperatureover a 3 h period. The reaction mixture was concentrated and takenforward crude.

B.3-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a stirred solution of 55.8 g (0.28 mol) of4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 25.7 g (0.29mol) of morpholine in benzene (125 mL) was added a catalytic amount(˜0.25 g) of p-toluenesulfonic acid. The mixture was heated to refluxfor 10 h under a Dean-Stark trap. The solvent was removed under reducedpressure to give a brown oil. The crude product was diluted with CH₂Cl₂(400 mL), and 46.83 mL (0.34 mol) of Et₃N was added. The mixture wascooled to 0° C., and a solution of 4-chloro-3-methyl-benzoyl chloride(0.35 mol) in CH₂Cl₂ (200 mL) was added slowly by dropping funnel over 2h. The reaction mixture was poured over water (400 mL) and the CH₂Cl₂layer was separated, dried (Na₂SO₄), and concentrated. The resulting oilwas taken up in EtOH (400 mL) and treated with 35 mL of hydrazine at 0°C. The reaction mixture was allowed to warm to room temperature andstirred for 17 h, during which time a white precipitate formed. Thevolume of the reaction mixture was reduced to ˜150 mL, and Et₂O (750 mL)was added. The suspension was stirred vigorously for 2 h and wasfiltered then washed with Et₂O (2×200 mL) and dried under vacuum toafford 50.74 g (52% over 3 steps) of3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester as a pale orange solid. MS (electrospray): exactmass calculated for C₁₈H₂₂ClN₃O₂, 347.1; m/z found, 348.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.26-7.43 (m, 4H), 4.65 (br s, 2H), 3.73 (br s, 2H),2.77 (br s, 2H), 2.34 (s, 3H), 1.49 (s, 9H).

C.3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a solution of3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 mL,526 mmol) in DMF (100 mL) was added cesium carbonate (20.56 g, 63 mmol).The reaction mixture was allowed to stir for 72 h, diluted with EtOAc(200 mL) and washed with saturated NaHCO₃ and brine. The organic layerwas dried over Na₂SO₄, concentrated and purified by columnchromatography (silica, 20% acetone/CH₂Cl₂) to afford3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (12.0 g, 57%). TLC (silica, 20% acetone/CH₂Cl₂):R_(f)=0.68. MS (electrospray) m/z 491.2 (491.2, calculated forC₂₇H₃₁ClN₆O, [M+H]⁺). ¹H NMR (400 MHz, CDCl₃) 7.55 (s, 1H), 7.36 (m,2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H), 4.11 (dd, J=14.3, 5.7 Hz, 1H),3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J=4.5 Hz, 1H), 2.75 (m, 2H),2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).

D.3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (5.33 g, 13.2 mmol) and1-(2-cyanophenyl)-piperazine (2.97 g, 15.86 mmol) were partiallydissolved in EtOH (50 mL) and triethylamine (2 mL). The reaction mixturewas heated to 80° C. for 18 h. The mixture was concentrated and purifiedby column chromatography (silica, 20% acetone/CH₂Cl₂) to give3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (6.51 g, 83%) as a yellow solid. TLC (silica, 20%acetone/CH₂Cl₂): R_(f)=0.35. MS (electrospray): m/z 591.3 (591.3,calculated for C₃₂H₃₉ClN₆O₃, [M+H]⁺).

E.2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile

3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.26 g, 2.13 mmol) was dissolved intrifluoroacetic acid (3 mL) and CH₂Cl₂ (3 mL) and allowed to stir for 2h. The reaction mixture was concentrated, taken up in EtOAc (50 mL) andwashed with aqueous NaHCO₃ (2×25 mL). The EtOAc layer was dried overNa₂SO₄ and concentrated to give2-(4-{3-[3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile(1.05 g, 99%) as a yellow foam. TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.27. MS (electrospray): m/z 491.2 (491.2, calculated forC₂₇H₃₁ClN₆O, [M+H]⁺). ¹H NMR (400 MHz, CDCl₃): 9.8 (br s, 1H), 7.55 (d,J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.2 Hz,1H), 7.20 (d, J=8.2 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.98 (d, J=8.2 Hz,1H), 4.56 (br s, 1H), 4.12-4.32 (m, 4H), 2.98-3.51 (m, 13H), 2.35 (s,3H).

F.(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-aceticacid methyl ester

2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile(58 mg, 0.118 mmol) was dissolved in CH₂Cl₂ (0.59 mL) and treated withmethyl chlorooxoacetate (16 mg, 0.129 mmol). The reaction mixture wasallowed to stir for 18 h at room temperature. Column chromatography(silica, 2-10% MeOH/CH₂Cl₂) gave(3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-aceticacid methyl ester (54 mg, 79%) as a white solid. MS (electrospray): m/z577.3 (577.2, calculated for C₃₀H₃₃ClN₆O₄, [M+H]⁺). ¹H NMR (400 MHz,CDCl₃): 7.32-7.62 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.2 Hz,1H), 4.59-4.80 (m, 3H), 4.12-4.28 (m, 2H), 3.92 (s, 3H), 3.78-3.86 (m,2H), 3.44-3.60 (m, 5H), 3.15-3.40 (m, 4H), 2.83-3.05 (m, 2H), 2.41 (s,3H).

Example 16

5-Methanesulfonyl-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineA. 1-Methanesulfonyl-piperidin-4-one

Potassium carbonate (324 g, 2340 mmol) was added to a solution of4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform(300 mL) and water (300 mL). The slurry was cooled to 0° C. and treatedwith methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise additionover a 1 h period (gas evolution was observed). The reaction mixture wasallowed to shake for 72 h and was partitioned between CH₂Cl₂ (500 mL)and saturated aqueous NaHCO₃ (500 mL). The aqueous layer was extractedwith CH₂Cl₂ (3×200 mL). The organic layer was washed with 1% KHSO₄ (250mL), dried (Na₂SO₄), and concentrated to afford 90.5 g (87%) of a whitesolid. MS (electrospray): exact mass calculated for C₆H₁₁NO₃S, 177.1;m/z found, 178.1 [M+H]⁺. HPLC (reverse phase conditions): t_(R)=2.19min. ¹H NMR (400 MHz, CDCl₃): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59(t, J=6.3 Hz, 4H).

B.5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

p-Toluenesulfonic acid (1.34 g. 7.0 mmol) and morpholine (25.83 mL, 296mmol) were added to a solution of 1-methanesulfonyl-piperidin-4-one(50.0 g. 282 mmol) in benzene (282 mL). The reaction mixture was heatedin a flask equipped with a condenser and a Dean-Stark trap at reflux for15 h. The reaction mixture was cooled and concentrated in vacuo to givethe enamine which was used without further purification. The enamine wasdissolved in CH₂Cl₂ (200 mL) and cooled to 0° C. To this was addedtriethylamine (47.2 mL, 339 mmol) followed by dropwise addition of4-trifluoromethylbenzoyl chloride (42.3 mL, 285 mmol) dissolved inCH₂Cl₂ (82 mL). The reaction mixture was allowed to warm to roomtemperature and stirred for 20 h. The reaction mixture was washed with 1N aqueous HCl (250 mL) and the CH₂Cl₂ layer was separated, dried(Na₂SO₄), and concentrated. The resulting oil was taken up in EtOH (300mL) and treated with hydrazine (44.3 mL, 1.41 mol) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 24 h.The mixture was concentrated and the resulting solid was filtered withEtOH wash and dried in vacuo to afford 70 g (72%) of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineas a white solid. MS (electrospray): exact mass calculated forC₁₄H₁₄F₃N₃O₂S, 345.0; m/z found, 346.0 [M+H]⁺. HPLC (reverse phaseconditions): t_(R)=6.33 min. ¹H NMR (400 MHz, CDCl₃): 7.72 (s, 4H), 4.58(s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.99 (t, J=5.7 Hz, 2H), 2.92 (s, 3H).

C.3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol

Cs₂CO₃ (33.74 g, 103.5 mmol) was added to a solution of5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min.3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirredunder N₂ at room temperature for 18 h. Water (500 mL) was added to thereaction and stirred for 5 min. The precipitated material was filteredout and washed with water (4×100 mL) and dried in a Freeze DryingSystem. The crude material (31.0 g) was taken up in anhydrous DMF (65mL) and Cs₂CO₃ (33.74 g, 103.5 mmol) was added, and stirred for 10 min.3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g,148 mmol) were added and stirring continued under N₂ at room temperaturefor 15 h. Water (500 mL) was added to the reaction and stirred for 10min. The precipitated material was filtered and washed with water (3×100mL). The filter cake was dissolved in CH₂Cl₂ (200 mL) and washed withbrine (50 mL), dried (Na₂SO₄), and concentrated. The solid wastriturated with Et₂O (200 mL), filtered, washed with Et₂O, and dried tofurnish 16.0 g of the desired compound. The mother liquor waschromatographed (silica, 0-10% acetone/EtOAc) to obtain an additional3.0 g of the title compound. The combined yield was 54.6%. MS(electrospray): calculated for C₁₇H₂₀F₃N₃O₃S, 403.12; m/z found, 404.0[M+H]⁺, 426.0 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.71 (d, J=8.2 Hz, 2H),7.66 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63(m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H),2.06 (q, J=6.1 Hz, 2H).

D.3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-Propionaldehyde

Dess-Martin periodinane (3.45 g, 8.2 mmol) was added to a solution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol(3.0 g, 7.4 mmol) in CH₂Cl₂ (20 mL) at 0° C. under N₂. After 15 min, thereaction was allowed to warm to room temperature and stirred for another1.5 h. The reaction was diluted with Et₂O (60 mL) and 20% aq. NaHCO₃ (35mL) was added slowly. Then Na₂S₂O₃ was added and stirred at roomtemperature for 30 min. The layers were separated and the aqueousportion was extracted with Et₂O (2×30 mL). The combined organic extractswere washed with brine, dried (Na₂SO₄) and concentrated. MPLC (1-10%MeOH/CH₂Cl₂) afforded 2.53 g of the desired aldehyde in 85% yield. MS(electrospray): calculated for C₁₇H₁₈F₃N₃O₃S, 401.11; m/z found, 402.1[M+H], 434.1 [M+MeOH+H]. ¹H NMR (400 MHz, CDCl₃): 9.82 (s, 1H), 7.63 (d,J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 4.25 (t, J=6.1 Hz,2H), 3.63 (t, J=5.8 Hz, 4H), 3.14 (t, J=6.1 Hz, 2H), 2.92 (t, J=5.8 Hz,2H), 2.81 (s, 3H).

E.5-Methanesulfonyl-[1-3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl]-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde(0.060 g, 0.15 mmol) and 1-(2-nitro-phenyl)-piperazine (0.032 g, 0.157mmol) in CH₂Cl₂ (0.5 mL), glacial AcOH (8.5 μL, 0.15 mmol) was added andstirred for 15 min at room temperature. NaBH(OAc)₃ (0.041 g, 0.19 mmol)was added and stirred under nitrogen overnight. Saturated NaHCO₃ (0.5mL) was then added and stirred for 15 min. The layers separated and theaqueous layer was extracted with CH₂Cl₂ (0.5 mL). MPLC purification(silica, 2-15% MeOH/CH₂Cl₂) afforded the desired product as a whitesolid (0.063 g, 71%). TLC (silica, 12% MeOH/CH₂Cl₂): R_(f)=0.67. MS(electrospray): exact mass calculated for C₂₇H₃₁F₃N₆O₄S, 592.21; m/zfound, 593.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.80 (dd, J=1.6, 8.2 Hz,1H), 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.52 (ddd, J=1.6,7.3, 8.3 Hz, 1H), 7.19 (dd, J=1.2, 8.3 Hz, 1H), 7.09 (m, 1H), 4.59 (s,2H), 4.17 (t, J=6.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.13 (br t, J=4.8Hz, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J=4.4 Hz,4H), 2.51 (t, J=7.0 Hz, 2H), 2.17 (q, J=6.9 Hz, 2H).

Example 17

1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-ureaA. 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester

To a stirred solution of 1,2-dichloro-3-nitrobenzene (0.96 g, 5.0 mmol)and piperazine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol) inacetonitrile (5 mL) was added of K₂CO₃ (1.38 g, 10 mmol). The mixturewas heated at reflux for 48 h. The solvent was removed under reducedpressure. The crude material was partitoned between EtOAc (100 mL) andH₂O (20 mL). The organic layer was washed with H₂O (2×20 mL), dried overNa₂SO₄ and concentrated. Column chromatography (silica, 10-20%EtOAc/hexanes) provided4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester (1.2 g, 70%). TLC (silica, 20% EtOAc/hexanes): R_(f)=0.45. MS(electrospray): exact mass calculated for C₁₅H₂₀ClN₃O₄, 341.1; m/zfound, 364.1 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃) 7.56 (dd, J=8.2, 1.4 Hz,1H), 7.50 (dd, J=8.2, 1.4 Hz, 1H), 7.13 (t, J=8.2 Hz, 1H), 3.38-3.56 (m,4H), 3.06 (m, 4H), 1.48 (s, 9H).

B. 1-(2-chloro-6-nitro-phenyl)-piperazine

4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester (1.87 g, 5.47 mmol) was dissolved in trifluoroacetic acid (5.0 mL)and CH₂Cl₂ (5.0 mL) and allowed to stir for 2 h. The reaction mixturewas concentrated, diluted with EtOAc, and washed with saturated aq.NaHCO₃. The organic layer was dried over Na₂SO₄, concentrated andpurified by column chromatography (silica, 100% CH₂Cl₂) to afford1-(2-chloro-6-nitro-phenyl)-piperazine (1.26 g, 95%). MS (electrospray):exact mass calculated for C₁₀H₁₂ClN₃O₂, 241.1; m/z found, 242.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.54 (dd, J=8.2, 1.6 Hz, 1H), 7.49 (dd, J=8.2,1.6 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 3.08 (br s, 4H), 2.99 (br s, 4H),2.07-2.12 (m, 1H).

C.1-{3-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde(0.5 g, 1.25 mmol) and 1-(2-chloro-6-nitrophenyl)-piperazine (0.301 g,1.25 mmol) in CH₂Cl₂ (6 mL) was added sodium sulfate (0.354 g, 2.50mmol) and sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The mixturewas allowed to stir at room temperature overnight. The mixture wasdiluted with CH₂Cl₂ and washed with water. The CH₂Cl₂ layer was driedover Na₂SO₄, and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography (silica, 10%acetone/CH₂Cl₂) to afford of1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(0.380 g, 49%). MS (electrospray): exact mass calculated forC₂₇H₃₀ClF₃N₆O₄S, 626.2; m/z found, 627.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.54 (dd, J=8.2,1.2 Hz, 1H), 7.49 (dd, J=8.2, 1.2 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 4.58(s, 2H), 4.13 (t, J=6.5 Hz, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.01-3.11 (m,4H), 2.95 (t, J=5.9 Hz, 2H), 2.92 (s, 3H), 2.42-2.53 (m, 4H), 2.40 (t,J=6.5 Hz, 2H), 2.12 (q, J=6.5 Hz, 2H).

D.3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine

To a stirred solution of1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(0.153 g, 0.244 mmol) in EtOH (2.44 mL) was added zinc dust (0.80 mg,1.22 mmol) and slow addition of acetic acid (0.70 mL). After 15 min theyellow solution became colorless and the access zinc dust was filteredthrough a plug of celite. The filtrate was concentrated and the residuewas purified by column chromatography (silica, 0-10% MeOH/CH₂Cl₂) toafford3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine(0.146 g, 100%). MS (electrospray): exact mass calculated forC₂₇H₃₂ClF₃N₆O₂S, 596.2; m/z found, 597.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 6.88 (t, J=8.2Hz, 1H), 6.63 (t, J=7.6 Hz, 2H), 4.55 (s, 2H), 4.36 (s, 2H), 4.15 (t,J=6.5 Hz, 2H), 3.60-3.70 (m, 4H), 2.97 (t, J=5.3 Hz, 2H), 2.90 (s, 3H),2.83 (d, J=10.8 Hz, 2H), 2.74 (d, J=11.5 Hz, 2H), 2.37 (t, J=6.6 Hz,2H), 2.11-2.20 (m, 4H).

E.1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl-3-methyl-urea

To a stirred solution of3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine(0.062 g, 0.104 mmol) in CH₂Cl₂ (0.52 mL) was added trimethylsilylisocyanate (0.017 mL, 0.125 mmol). The reaction mixture was allowed tostir for 48 h at room temperature. The reaction had not gone tocompletion, so an additional 0.017 mL (0.125 mmol) of trimethylsilylisocyanate was added and the reaction was heated to 45° C. for 10 h.Column chromatography (silica, 3-10% MeOH/CH₂Cl₂) afforded1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-urea(0.015 g, 22%). MS (electrospray): exact mass calculated forC₂₈H₃₃ClF₃N₇O₃S, 639.2; m/z found, 640.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.26 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H),7.66 (d, J=8.2 Hz, 2H), 7.09 (t, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H),4.65 (s, 2H), 4.55 (s, 2H), 4.15 (t, J=6.7 Hz, 2H), 3.65-3.73 (m, 4H),2.96 (t, J=5.6 Hz, 2H), 2.87-2.92 (m, 2H), 2.91 (s, 3H), 2.70 (d, J=11.4Hz, 2H), 2.40 (t, J=6.7 Hz, 2H), 2.09-2.22 (m, 4H).

Example 18

1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide A.3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To a stirred solution of 500 g (2.51 mol) of1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholinein benzene (1.25 L) was added a catalytic amount (˜0.25 g) of p-TsOH.The mixture was heated to reflux for 36 h with a Dean-Stark trap. Onehalf of the solvent was removed under reduced pressure and the resultingsolution was cooled and filtered. The filtrate was then concentrated toyield 630 g (94%) of an orange red oil. The eneamine was divided and 320g (1.19 mol) was diluted with CH₂Cl₂ (1.0 L) and 165.0 mL (1.19 mol) ofEt₃N was added. The mixture was cooled to 0° C. and a solution of 225 g(1.08 mol) of 4-trifluoromethylbenzoyl chloride in CH₂Cl₂ (0.5 L) wasadded slowly by dropping funnel over 1 h. The mixture was allowed towarm to rt and stir overnight. The reaction was then diluted with 1 NHCl (450 mL) and stirred vigorously for 3 h. The aqueous layer wasextracted with CH₂Cl₂ (3×500 mL) and the combined extracts were driedover Na₂SO₄ and the solvent was removed under reduced pressure. Thecrude oil was diluted with EtOH (1 L) and cooled to 0° C. To thisstirred solution was slowly added 115 g (3.57 mol) of hydrazine and themixture was allowed to warm to rt and stir overnight during which time awhite precipitate formed. The volume of the reaction was reduced to ˜500mL and cooled. The precipitate was collected to afford 285 g (72% fromeneamine) of a white solid. ¹H NMR (400 MHz, CDCl₃): 7.63-7.55 (m, 4H),4.58 (br s, 2H), 3.69-3.62 (br m, 2H), 2.74-2.68 (br m, 2H), 1.47 (s,9H).

B.1-(2-Methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-Phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0.50 mL,5.6 mmol) were combined in toluene (30 mL) and heated to 75° C. Theresulting mixture was treated with t-BuONa (100 mg), and heatingcontinued for 48 h. The mixture was allowed to cool and partitionedbetween EtOAc (300 mL) and NaHCO₃ (75 mL). The aqueous layer wasextracted with EtOAc (3×75 mL). The combined extracts were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 30-60%EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC (silica,50% EtOAc/hexanes): R_(f)=0.4. MS (electrospray): m/z calculated forC₂₂H₂₇F₃N₃O₄ [M⁺+H] 454.20, found 454.1. ¹H NMR (CDCl₃, 400 MHz): 7.75(br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t, J=6.6Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz, 2H), 2.79 (brt, J=5.6 Hz, 2H), 1.48 (s, 9H).

C.1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A solution of LiBH₄ (26 mg, 1.2 mmol) in THF (0.5 mL) was added to a 0°C. solution of1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (317 mg, 0.70 mmol) in THF (4.0 mL). The mixturewas stirred for 5 min then additional LiBH₄ (15 mg) was added andstirring continued for 17 h. The mixture was partitioned between EtOAc(80 mL) and saturated aqueous NaHCO₃ (20 mL). The aqueous layer wasextracted with EtOAc (2×20 mL). The combined extracts were dried overNa₂SO₄ and concentrated. Column chromatography (silica, 0-8%MeOH/CH₂Cl₂) afforded 268 mg (95%) of the title compound. HPLC (reversephase conditions), t_(R)=6.82 min. MS (electrospray): m/z calculated forC₂₁H₂₆F₃N₃O₃ [M⁺+Na] 448.18, found 448.10. ¹H NMR (CDCl₃, 400 MHz): 7.73(br d, J=8.2 Hz, 2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J=6.4Hz, 2H), 3.76 (br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J=5.4 Hz,2H), 2.04 (q, J=6.1, 2H), 1.48 (s, 9H).

D.1-(3-Oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise to astirred solution of1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.30 g, 3.05 mmol) in CH₂Cl₂ (15 mL) at 0° C.under N₂. Then the reaction was stirred at 0° C. for 15 min and allowedto warm to room temperature. After stirring at room temperature for 1.5h the reaction was diluted with Et₂O (50 mL) and saturated NaHCO₃ (15mL) was added slowly (caution! gas evolution). Then Na₂S₂O₃.5H₂O (5.31g, 21.4 mmol) was added and stirred for 30 min. The layers wereseparated and the aqueous layer was extracted with Et₂O (2×30 mL). Thecombined extracts were washed with brine, dried (Na₂SO₄) andconcentrated. MPLC (1-10% MeOH/CH₂Cl₂) afforded the aldehyde in 79%yield (1.02 g). TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.67. MS(electrospray) calculated for C₂₁H₂₄F₃N₃O₃, 424.2 ([M+H]⁺), m/z found,424.2. ¹H NMR (400 MHz, CDCl₃): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H),7.54 (br s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H),3.04 (t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).

E. 4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester

To a stirred solution of 0.96 g (5.0 mmol) of1,2-dichloro-3-nitrobenzene and 0.93 g (5.0 mmol, 1 eq) of1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38g (10 mmol, 2 eq) of K₂CO₃. The mixture was heated to reflux for 48 h.The solvent was removed under reduced pressure. The crude product waspartitioned between EtOAc (100 mL) and 20 mL of H₂O. The organic layerwas washed with H₂O (2×20 mL), dried over Na₂SO₄ and concentrated.Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.2 g(70%) of 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester. TLC (silica, 20% EtOAc/hexanes): R_(f)=0.45. ¹H NMR(400 MHz, CDCl₃): 7.56 (dd, J=8.2, 1.4 Hz, 1H), 7.50 (dd, J=8.2, 1.4 Hz,1H), 7.13 (t, J=8.2 Hz, 1H), 3.56-3.38 (m, 4H), 3.10-3.00 (m, 4H), 1.48(s, 9H).

F.1-{3-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester (940 mg, 2.75 mmol) in 10 mL of CH₂Cl₂ was treated with 5 mL oftrifluoroacetic acid and stirred at 25° C. for 1 h. The volatiles werethen removed. The residue was taken up in CH₂Cl₂ (60 mL) and KOH (4 N,20 mL). The organic layer was separated, dried over Na₂SO₄, andconcentrated. The yellow oil was dissolved in CH₂Cl₂ and added into the996 mg (2.35 mmol) of1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. The yellow solution was treated with glacialacetic acid (0.8 mL, 6 eq) and stirred at 25° C. for 1 h. NaBH(OAc)₃(1.5 g, 7.05 mmol) was added and stirred under nitrogen for 2 h. Thensaturated NaHCO₃ (20 mL) was added and stirred for 30 min, and thelayers were separated. The organic extract was washed with brine, driedover Na₂SO₄, and concentrated under reduced pressure. Columnchromatography (silica, 2-5% MeOH/CH₂Cl₂) afforded1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester as a white solid (1.40 g, 92%). TLC (silica, 5%MeOH/CH₂Cl₂): R_(f)=0.3. MS (electrospray): exact mass calculated forC₃₁H₃₆ClF₃N₆O₄, 648.24; m/z found 649.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.69 (d, J=8.2 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 4H), 7.02 (t,J=8.2 Hz, 1H), 4.58 (br s, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.73-3.65 (m,2H), 3.05-2.95 (m, 4H), 2.71 (t, J=5.6 Hz, 2H), 2.50-2.35 (m, 4H), 2.30(t, J=6.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.41 (s, 9H).

G.1-{3-[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A solution of 360 mg (0.56 mmol) of1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester in 4 mL of MeOH was treated with 182 mg (5 eq) ofzinc dust and glacial acetic acid (1.57 mL, 50 eq) at 25° C. Thereaction mixture was stirred at 25° C. for 1 h. The reaction mixture wasthen filtered through a pad of celite and concentrated to obtain a thickoil. The residue was taken up in CH₂Cl₂ (50 mL) and sat. NaHCO₃ (20 mL).The organic layer was separated, washed with H₂O (2×10 mL), dried overNa₂SO₄, and concentrated to afford1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): exact mass calculated for C₃₁H₃₈ClF₃N₆O₂, 618.27; m/zfound, 619.3 [M+H]⁺.

H.1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A solution of1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (257 mg, 0.42 mmol) in 4 mL of CH₂Cl₂ was treatedwith 32 □L (0.42 mmol, 1.0 eq) of methanesulfonyl chloride and 116]L(0.83 mmol, 2 eq) of triethylamine and the reaction mixture stirred at25° C. for 1 h. EtOAc (40 mL) and sat. NaHCO₃ (20 mL) were added. Theorganic layer was separated and washed with H₂O (20 mL), brine (20 mL),dried over Na₂SO₄, and concentrated to afford the crude1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. TLC (silica, 10% MeOH/CH₂Cl₂): R_(f)=0.3. MS(electrospray): exact mass calculated for C₃₂H₄₀ClF₃N₆O₄S, 696.25; m/zfound, 697.2 [M+H]⁺.

I.1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-tert-butoxycarbonyl-sulfonicacid amide

A solution of 97 mg (0.14 mmol) of1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester in 3 mL of CH₂Cl₂ was treated with 1.5 mL oftrifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 hbefore all volatiles were removed. To this crude material in 0.5 mL ofCH₂Cl₂ was added dropwise a premixed solution of chlorosulfonylisocyanate (18 μL, 0.209 mmol) and 2-methyl-2-propanol (20 μL, 0.209mmol) in CH₂Cl₂ (0.150 mL). The reaction mixture was allowed to stir at25° C. overnight. Preparative TLC (silica, 2-10% MeOH/CH₂Cl₂) providedthe title compound (84 mg, 78%). TLC (silica, 10% MeOH/CH₂Cl₂):R_(f)=0.3. MS (electrospray): exact mass calculated forC₃₂H₄₁ClF₃N₇O₆S₂, 775.22; m/z found, 776.2 [M+H]⁺.

J.1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide

1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-tert-butoxycarbonyl-sulfonicacid amide (84 mg, 0.11 mmol) was dissolved in trifluoroacetic acid(0.75 mL) and CH₂Cl₂ (0.75 mL). The reaction mixture was allowed to stirat 25° C. for 2 h. Removal of volatiles under a stream of nitrogenprovided1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide in quantitative yield as a trifluoroacetic acid salt. MS(electrospray): exact mass calculated for C₂₇H₃₃ClF₃N₇O₄S₂, 675.17; m/zfound, 676.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.73 and 7.63 (AB pattern,J=8.2 Hz, 4H), 7.37 (d, J=7.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.04 (d,J=7.8 Hz, 1H), 4.32 (s, 2H), 4.20 (t, J=6.3 Hz, 2H), 3.87-3.80 (m, 2H),3.80-3.75 (m, 4H), 3.70-3.25 (m, 7H), 3.00-2.75 (m, 4H), 2.25-2.15 (m,2H).

Example 19

N-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamideA.5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(10.0 g, 29.0 mmol) and epichlorohydrin (24 mL, 307 mmol) were setstirring in DMF (150 mL) containing Cs₂CO₃ (10.4 g, 31.9 mmol). Afterstirring at room temperature for 4 days the mixture was evaporated,brought up in EtOAc and washed with water. The organics were dried(MgSO₄) and evaporated to give a light yellow solid. Columnchromatography (silica, 5% acetone/CH₂Cl₂) gave 4.1 g (35%) of a whitesolid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.28. MS (electrospray):exact mass calculated for C₁₇H₁₈F₃N₃O₃S, 401.10; m/z found, 402.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.84 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J=5.4 Hz, 1H), 3.90-3.70 (m, 2H),3.47 (m, 1H), 3.10-2.9 (m, 6H), 2.65-2.60 (m, 1H).

B. 4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester

To a stirred solution of 0.96 g (5.0 mmol) of1,2-dichloro-3-nitrobenzene and 0.93 g (5.0 mmol, 1 eq) of1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38g (10 mmol, 2 eq) of K₂CO₃. The mixture was heated to reflux for 48 h.The solvent was removed under reduced pressure. The crude product waspartitioned between EtOAc (100 mL) and 20 mL of H₂O. The organic layerwas washed with H₂O (2×20 mL), dried over Na₂SO₄ and concentrated.Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.2 g(70%) of 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester. TLC (silica, 20% EtOAc/hexanes): R_(f)=0.45. ¹H NMR(400 MHz, CDCl₃): 7.56 (dd, J=8.2, 1.4 Hz, 1H), 7.50 (dd, J=8.2, 1.4 Hz,1H), 7.13 (t, J=8.2 Hz, 1H), 3.56-3.38 (m, 4H), 3.10-3.00 (m, 4H), 1.48(s, 9H).

C. 4-(2-Amino-6-chloro-phenyl)-piperazine-1-carboxylic acid tert-butylester

A solution of 342 mg (1 mmol) of4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester in 5.0 mL of MeOH was treated with 630 mg (10 mmol, 10 eq) ofammonium formate and a catalytic amount of 10% Pd—C (34 mg). Thereaction mixture was stirred at 65° C. for 30 min. The reaction mixturewas then filtered through a pad of celite and concentrated to obtain ayellow solid. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.40. MS(electrospray): exact mass calculated for C₁₅H₂₂ClN₃O₂, 311.14; m/zfound, 312.1 [M+H]⁺.

D. 4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

4-(2-Amino-6-chloro-phenyl)-piperazine-1-carboxylic acid tert-butylester (163 mg, 0.53 mmol) in CH₂Cl₂ was treated with 62 □L (0.80 mmol,1.5 eq) of methanesulfonyl chloride and 148 □L (1.06 mmol, 2 eq) oftriethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc(40 mL) and sat. NaHCO₃ (20 mL) were added. The organic layer wasseparated and washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄,and concentrated. Column chromatography (silica, 0-5% acetone/CH₂Cl₂)provided 145 mg (70%) of4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester. TLC (silica, 5% acetone/CH₂Cl₂): R_(f)=0.35. MS(electrospray): exact mass calculated for C₁₆H₂₄ClN₃O₄S, 389.12; m/zfound, 388.1 (negative). ¹H NMR (400 MHz, CDCl₃): 7.41 (dd, J=8.2, 1.6Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 4.25-3.91(m, 2H), 3.66-3.52 (m, 2H), 3.01 (s, 3H), 3.01-2.84 (m, 2H), 2.70-2.56(m, 2H), 2.55-2.43 (m, 2H), 1.44 (s, 9H).

E.N-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide

4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (145 mg, 0.37 mmol) was dissolved in 3 mL of CH₂Cl₂ andtreated with 1.5 mL of trifluoroacetic acid. The reaction mixture wasstirred at 25° C. for 1 h before all volatiles were removed. The solidwas treated with CH₂Cl₂ (20 mL) and aqueous KOH (4 N, 10 mL). Theorganic layer was separated, dried over Na₂SO₄, and concentrated. Thecrude oil (90 mg) was dissolved in absolute EtOH (1.0 mL) and treatedwith 96 mg (0.24 mmol) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.The reaction mixture was refluxed at 85° C. for 3 h and then the solventwas removed. Column chromatography (silica, 0-5% MeOH/CH₂Cl₂) provided138 mg (20% over 4 steps) ofN-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide.TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.45. MS (electrospray): exact masscalculated for C₂₈H₃₄ClF₃N₆O₅S₂, 690.17; m/z found, 691.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.28 (s, 1H), 7.65 and 7.59 (AB pattern, J=8.4 Hz,4H), 7.36 (d, J=8.1 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.2 Hz,1H), 4.54-4.44 (m, 2H), 4.21-3.94 (m, 3H), 3.77-3.52 (m, 4H), 3.41 (m,2H), 2.96 (s, 3H), 2.81 (s, 3H), 3.05-2.73 (m, 4H), 2.66-2.20 (m, 4H).

Example 20

1-[4-(2,6-Dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olA. 4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1.01 g (5.0 mmol) of1-chloro-2,6-dinitrobenzene and 0.93 g (5.0 mmol) of1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38g (10 mmol) of K₂CO₃. The mixture was heated to reflux for 48 h. Thesolvent was removed under reduced pressure. The crude product waspartitioned between EtOAc (100 mL) and 20 mL of H₂O. The organic layerwas washed with H₂O (2×20 mL), dried over Na₂SO₄ and concentrated.Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.31 g(85%) of 4-(2,6-dinitro-phenyl)-piperazine-1-carboxylic acid tert-butylester TLC (silica, 20% EtOAc/hexanes): R_(f)=0.35. ¹H NMR (400 MHz,CDCl₃): 7.75 (d, J=8.2 Hz, 2H), 7.25 (t, J=8.2 Hz, 1H), 3.30 (m, 4H),2.95 (m, 2H), 1.44 (s, 9H).

B.1-[4-(2,6-Dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol

4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester(220 mg, 0.63 mmol) was dissolved in 5.0 mL of CH₂Cl₂ and treated with3.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 25°C. for 1 h before all volatiles were removed. The solid was treated withCH₂Cl₂ (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer wasseparated, dried over Na₂SO₄, and concentrated. The crude oil (67 mg)was dissolved in absolute EtOH (1.2 mL) and treated with 141 mg (0.35mmol, 1.3 eq) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.The reaction mixture was refluxed at 85° C. for 3 h and then the solventwas removed. Column chromatography purification (silica, 10-20%acetone/CH₂Cl₂) provided 150 mg (85%) of1-[4-(2,6-dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.TLC (silica, 10% acetone/CH₂Cl₂): R_(f)=0.3. MS (electrospray): exactmass calculated for C₂₇H₃₀F₃N₇O₇S, 653.19; m/z found, 654.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.71 (d, J=8.2 Hz, 2H), 7.64 and 7.58 (AB pattern,J=8.4 Hz, 4H), 7.20 (t, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H),3.66 (t, J=5.3 Hz, 2H), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m,4H).

Example 21

2-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-methanesulfonylamino-benzoicacid methyl ester A.4-(2-Methoxycarbonyl-6-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

To a stirred solution of 736 mg (2.83 mmol) of ethyl2-bromo-3-nitrobenzoate and 579 mg (3.1 mmol, 1.1 eq) of1-tert-butyloxycarbonylpiperazine in n-butanol (6 mL) was added 330 mg(3.1 mmol, 1.1 eq) of Na₂CO₃. The mixture was heated to reflux for 4 h.The solvent was removed under reduced pressure. The crude product waspartitioned between EtOAc (100 mL) and 20 mL of H₂O. The organic layerwas washed with H₂O (2×20 mL), dried over Na₂SO₄ and concentrated.Column chromatography (silica, 10-20% EtOAc/hexanes) provided 744 mg(72%) of 4-(2-methoxycarbonyl-6-nitro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester. TLC (silica, 20% EtOAc/hexanes): R_(f)=0.5. ¹HNMR (400 MHz, CDCl₃): 7.67 (dd, J=8.2, 1.4 Hz, 1H), 7.62 (dd, J=8.2, 1.4Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.44-3.36 (m, 4H),3.03-2.95 (m, 4H), 1.48 (s, 9H).

B.2-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-Phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-methanesulfonylamino-benzoicacid methyl ester

A solution of 1.0 g (2.73 mmol) of4-(2-methoxycarbonyl-6-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester in 18 mL of MeOH was treated with 893 mg (13.7 mmol, 5eq) of zinc dust and glacial acetic acid (8 mL). The reaction mixturewas stirred at 25° C. for 1 h. The reaction mixture was then filteredthrough a pad of celite and concentrated to obtain a thick oil. Theresidue was taken up in EtOAc (200 mL) and sat. NaHCO₃ (100 mL). Theorganic layer was separated, washed with H₂O (2×50 mL), dried overNa₂SO₄, and concentrated. Column chromatography (silica, 10-30%EtOAc/hexanes) provided the desired amine (844 mg, 92%). The amine (42mg, 0.13 mmol) in CH₂Cl₂ (0.5 mL) was treated with 9.7 μL (0.13 mmol,1.0 eq) of methanesulfonyl chloride and 34.9 μL (0.25 mmol, 2 eq) oftriethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc(20 mL) and sat. NaHCO₃ (10 mL) were added. The organic layer wasseparated and washed with H₂O (10 mL), brine (20 mL), dried over Na₂SO₄,and concentrated. The crude oil was dissolved in 2 mL of CH₂Cl₂ andtreated with 0.5 mL of trifluoroacetic acid. The reaction mixture wasstirred at 25° C. for 1 h before all volatiles were removed. The crudeoil was dissolved in absolute EtOH (1.0 mL) and treated with 40 mg (0.1mmol) of5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineand 200 μL of triethylamine. The reaction mixture was refluxed at 85° C.for 4 h and then the solvent was removed. Preparative TLC (silica, 7%MeOH/CH₂Cl₂) provided 35 mg (49% over 3 steps) of the title compound.TLC (silica, 5% MeOH/CH₂Cl₂): R_(f)=0.30. MS (electrospray): exact masscalculated for C₃₀H₃₇F₃N₆O₇S₂, 714.21; m/z found, 715.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.11 (s, 1H), 7.74-7.59 (m, 5H), 7.30 (d, J=8.1 Hz,1H), 7.21 (t, J=8.2 Hz, 1H), 4.62-4.49 (m, 2H), 4.25-3.99 (m, 3H), 3.90(s, 3H), 3.80-3.57 (m, 3H), 3.53-3.27 (m, 2H), 3.14-2.78 (m, 4H), 3.05(s, 3H), 2.86 (s, 3H), 2.76-2.65 (m, 2H), 2.61-2.20 (m, 4H).

Example 22

1-{3-[4-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineA. 3-piperazin-1-yl-benzo[d]isothiazole 1,1-dioxide

POCl₃ (10.2 mL, 109.2 mmol) was added to saccharin (5.0 g, 27.3 mmol)and heated at 120° C. for 20 h. The excess reagent was removed in arotary evaporator and water (50 mL) was added to the residue to form aprecipitate. The solid was filtered, washed with water (2×20 mL), anddried. A portion of the above crude material (2.0 g, 9.95 mmol) andpiperazine (4.28 g, 49.75 mmol) was taken in dioxane (10 mL), and heatedat 100° C. for 24 h. The reaction was allowed to cool to roomtemperature and poured into ice water (50 g), and neutralized byaddition of 10% aqueous NaOH. The mixture was extracted with CH₂Cl₂(3×25 mL) and the combined organic extracts were washed with brine,dried (Na₂SO₄) and concentrated. MPLC (silica, 5-20% MeOH/CH₂Cl₂)afforded the piperazinyl derivative (0.07 g, 4.2%). MS (electrospray):exact mass calculated for C₁₁H₁₃N₃O₂S, 251.07; m/z found, 252.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.72 (dd, J=0.8, 7.4 Hz, 1H), 7.64 (d, J=7.8Hz, 1H), 7.49 (dt, J=0.8, 7.4 Hz, 1H), 7.43 (dt, J=1.2, 7.8 Hz, 1H),3.80 (s, 4H), 2.85 (br t, J=5.0 Hz, 4H), 2.07 (br s, 1H). ¹³C NMR (100MHz, CDCl₃): 160.8, 145.3, 133.3, 133.0, 128.5, 125.9, 123.2, 49.8,46.3.

B.1-{3-[4-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde(0.040 g, 0.13 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole1,1-dioxide (0.050 g, 0.21 mmol) in CH₂Cl₂ (0.5 mL), glacial AcOH (12μL, 0.21 mmol) was added and stirred for 15 min at room temperature.NaBH(OAc)₃ (0.058 g, 0.27 mmol) was added and stirred under nitrogenovernight. Saturated NaHCO₃ (0.5 mL) was then added and stirred for 15min. The layers separated and the aqueous layer was extracted withCH₂Cl₂ (0.5 mL). MPLC (silica, 2-15% MeOH/CH₂Cl₂) afforded the desiredproduct as a white solid (0.048 g, 76%). TLC (silica, 12% MeOH/CH₂Cl₂):R_(f)=0.50. MS (electrospray): exact mass calculated for C₂₈H₃₁F₃N₆O₄S₂,636.18; m/z found, 637.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.94 (dd,J=0.8, 7.6 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H),7.73-7.63 (m, 2H), 7.68 (d, J=8.3 Hz, 2H), 4.57 (s, 2H), 4.17 (t, J=6.9Hz, 2H), 4.04 (br s, 4H), 3.69 (t, J=5.7 Hz, 2H), 2.94 (s, 3H), 2.92 (t,J=6.2 Hz, 2H), 2.62 (t, J=5.0 Hz, 4H), 2.44 (t, J=6.6 Hz, 2H), 2.13 (q,J=6.6 Hz, 2H).

Example 23

1-[1-{3-[4-(6-Chloro-benzothiazol-2-yl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 6-Chloro-2-piperazin-1-yl-benzothiazole

To a stirred solution of 1.07 g (5.24 mmol) of 2,6-dichlorobenzothiazolein dry DMF (25 mL) was added 2.4 g of potassium carbonate (15.7 mmol)and 0.5 g of piperazine (5.8 mmol). The mixture was stirred at roomtemperature for 4 h. When the reaction was complete it was partitionedbetween EtOAc (150 mL) and water (50 mL) and separated. The aqueouslayer was extracted with EtOAC (2×100 mL). The combined organic layerswere then washed with water (2×25 mL), brine, dried over Na₂SO₄, and thesolvent was removed under reduced pressure to give 1.33 g (100%) ofdesired product as a white solid. MS (electrospray): exact masscalculated for C₁₁H₁₂ClN₃S, 253.04; m/z found, 254.0 [M+H]⁺.

B.1-[1-{3-[4-(6-Chloro-benzothiazol-2-yl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-Phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

To a stirred solution of 144 mg (0.39 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanonein 4 mL of EtOH was added 100 mg (0.39 mmol)6-chloro-2-piperazin-1-yl-benzothiazole. The solution was heated to 60°C. overnight. The solvent was then removed by rotary evaporation and thecrude product was purified by column chromatography (silica, 0-10%MeOH/EtOAc) to afford 220 mg (90%) of a white solid. MS (electrospray):exact mass calculated for C₂₉H₃₀ClF₃N₆O₂S: 618.18; m/z found, 619.2[M+H]⁺. HPLC (reverse phase conditions 40-90%): t_(R)=8.27 min. ¹H NMR(CDCl₃, 400 MHz, a mixture of amide rotamers): 7.70 (d, J=8.34 Hz, 1H),7.62 (m, 2H), 7.57 (d, J=8.59 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.36 (d,J=8.59 Hz, 1H), 7.16 (dd, J=8.59, 2.53 Hz, 1H), 4.80 and 4.68 (A and Bof AB quartet, J=15.92 Hz, 1H), 4.58 (s, 1H), 4.18-4.08 (m, 2H),4.01-3.89 (m, 2H), 3.85-3.60 (m, 2H), 3.59-3.47 (m, 4H), 2.94-2.75 (m,2H), 2.72-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.46-2.39 (m, 2H), 2.13 (s,1.5H), 2.08 (s, 1.5H).

Example 24

1-[1-[3-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneA. 4-Benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 100 mg (0.65 mmol) of3-chloro-1,2-benzisoxazole in pyridine (1 mL) was added 145 mg ofpiperazine-1-carboxylic acid tert-butyl ester (0.78 mmol) and 0.18 mL ofDBU (0.78 mmol). The mixture was stirred at 100° C. overnight and thenpartitioned between EtOAC (50 mL) and water (20 mL) and separated. Theaqueous layer was extracted with EtOAC (2×30 mL). The combined organiclayers were then washed with water (25 mL), brine, dried over Na₂SO₄,and the solvent was removed under reduced pressure to give crudeproduct. Purification by column chromatography (silica, 60-100%CH₂Cl₂/hexanes) gave 82 mg (42%) of the desired product as a lightyellow solid. MS (electrospray): exact mass calculated for C₁₆H₂₁N₃O₃,303.16; m/z found, 326.1 [M+Na]⁺. ¹H NMR (CDCl₃, 400 MHz): 7.68 (dt,J=8.02, 0.98 Hz, 1H), 7.52-7.44 (m, 2H), 7.24 (ddd, J=8.42, 6.46, 1.57Hz, 1H), 3.66-3.61 (m, 4H), 3.56-3.49 (m, 4H), 1.49 (s, 9H).

B.1-[1-[3-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-2-hydroxy-Propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

A solution of 82 mg (0.27 mmol) of4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in2 mL of CH₂Cl₂ was treated with trifluoroacetic acid (0.5 mL) at roomtemperature overnight. The solvent was then removed and the crudeproduct dissolved in EtOH and stirred over 100 mg of sodium bicarbonatefor 1 h, the solid was then filtered off and the filtrate concentrated.The crude piperazine was then dissolved in 4 mL EtOH and treated with100 mg (0.27 mmol) of1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.The solution was heated to 60° C. overnight. The solvent was thenremoved by rotary evaporation and the crude product was purified bycolumn chromatography (silica, 0-10% MeOH/EtOAc) to afford 105 mg (68%)of a white solid. MS (electrospray), exact mass calculated forC₂₉H₃₁F₃N₆O₃, 568.24; m/z found, 569.2 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, amixture of amide rotamers): 7.77 (d, J=8.41 Hz, 1H), 7.69 (m, 2H),7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m,1H), 4.93 (br m, 1H), 4.87 and 4.75 (A and B of AB quartet, J=15.65 Hz,1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2.3H), 4.09-3.95 (m, 1.7H),3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3.62-3.49 (m, 4H), 3.01-2.85(m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m, 2H), 2.58-2.45 (m, 2H),2.20 (s, 1.5H), 2.15 (s, 1.5H).

Example 25

1-[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 26

1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-ureaExample 27

1-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-ureaExample 28

3-Amino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzoicacid methyl ester Example 29

3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamineExample 30

1-[2-(4-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-3-chloro-phenyl]-3-methyl-ureaExample 31

1-{3-[4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 32

[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-carbamicacid methyl ester Example 33

1-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 34

2-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-3-nitro-benzoicacid methyl ester Example 35

1-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 36

2-(4-{2-Hydroxy-3-[3-(4-iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrileExample 37

3-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 38

2-(4-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 39

2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 40

1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 41

1-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 42

2-(4-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrileExample 43

N-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamideExample 44

3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 45

3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 46

Cathepsin S Inhibition Assay.

Recombinant human cathepsin S (CatS) was expressed in the baculovirussystem and purified in one step with a thiopropyl-sepharose column. 10-Lyielded ˜700 mg of CatS and N-terminal sequencing confirmed identity.The assay is run in 100 mM sodium acetate pH 5.0 containing 1 mM DTT and100 mM NaCl. The substrate for the assay is

-   -   (Aedens)EKARVLAEAA(Dabcyl)K-amide        The K_(m) for the substrate is around 5 μM but the presence of        substrate inhibition makes kinetic analysis difficult. With 20        μM substrate the assay rate is linear over the range of 1-8 ng        CatS in 100 μl reaction. Using 2 ng/well of CatS, the production        of product is linear and yields ˜7-fold signal after 20 min with        only 20% loss of substrate. Primary assays are run by quenching        the reaction after 20 min with 0.1% SDS and then measuring the        fluorescence. For other assays, measurements are taken every min        for 20 min. The rate is calculated from the slope of the        increase and the percent inhibition is calculated from this (See        Tables 1, 2 and 3 below).

TABLE 1 EXAMPLE IC₅₀ (μM) 1 0.89 2 1.22 3 0.84 4 0.51 5 0.36 6 0.30 76.60 8 0.89 9 1.14 10 0.05 11 0.03 12 0.98 13 0.77 14 0.25 15 0.12 160.06 17 0.08 18 0.14 19 0.06 20 0.17 21 0.07 22 2.15 23 1.10 24 0.47

TABLE 2 EXAMPLE IC₅₀ (μM) 25 0.04 26 0.04 27 0.04 28 0.07 29 0.07 300.08 31 0.10 32 0.10 33 0.10 34 0.11 35 0.12 36 0.12 37 0.12 38 0.12 390.13 40 0.13 41 0.13 42 0.13 43 0.13 44 0.13 45 0.13

Example 1011-(3-(4-Chloro-phenyl)-1-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1021-[1-(3-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-hydroxy-propyl)-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1031-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1041-(3-(4-Chloro-phenyl)-1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1051-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1061-(3-(4-Chloro-phenyl)-1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1071-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1081-(3-(4-Chloro-phenyl)-1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1091-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(3-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1101-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1111-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1121-[1-[3-(4-Benzhydryl-piperazin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1131-[3-(4-Chloro-phenyl)-1-(3-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1141-(3-(4-Chloro-phenyl)-1-{3-[4-(9H-fluoren-9-yl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1151-[1-[3-(4-Benzyl-piperazin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1163-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propan-1-oneExample 1171-[1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1181-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1191-(3-(4-Fluoro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1204-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butan-1-oneExample 1211-(1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-p-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1221-(3-(4-Chloro-phenyl)-1-{3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1231-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-pyridin-2-yl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1241-(3-Biphenyl-4-yl-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1251-(1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1261-[1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1271-[1-[2-Hydroxy-3-(4-pyridin-4-yl-piperazin-1-yl)-propyl]-3-(4-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1291-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-oneExample 1303-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1311-(1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-naphthalen-2-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1321-(3-(4-tert-Butyl-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1331-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-butan-1-oneExample 1341-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2,2-dimethyl-propan-1-oneExample 136(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-(4-methoxy-phenyl)-methanoneExample 1373-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 1381-[3-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propan-2-olExample 1391-(3-(3,4-Dichloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1401-[1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1411-[1-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1421-(3-(4-Chloro-phenyl)-1-{3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1432-(4-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 1444-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrileExample 1451-(3-(4-Chloro-phenyl)-1-{3-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1461-(3-(4-Chloro-phenyl)-1-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1471-(3-(4-Chloro-phenyl)-1-{3-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1481-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(3-methyl-4-p-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1491-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(3-methyl-4-m-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1501-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1511-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1521-(3-(4-Chloro-phenyl)-1-{3-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1531-(3-(4-Chloro-phenyl)-1-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-but-2-enyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1544-(5-Acetyl-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrileExample 1551-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1561-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1571-(3-(2,4-Bis-trifluoromethyl-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1581-(3-(2,4-Dichloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1592-(4-{3-[3-(4-Chloro-phenyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 160 2-(4-{3-[3-(4-Chloro-phenyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-phenol Example 1611-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1621-{3-(4-Chloro-phenyl)-1-[2-(2-methyl-allyloxy)-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1631-[1-[2-Benzyloxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 164 Acetic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester Example 165 Morpholine-4-carboxylic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester Example 166 Benzoic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester Example 167 Benzoyl-carbamic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester Example 1681-[3-(4-Chloro-phenyl)-pyrazol-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 1691-(3-(3-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1702-(4-{3-[5-Acetyl-3-(3-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 171 tert-Butyl-carbamic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester Example 172 Carbonic acid1-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethylester methyl ester Example 1731-(3-(4-Chloro-phenyl)-1-{4-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-but-2-enyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1742-(4-{4-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-but-2-enyl}-piperazin-1-yl)-benzonitrileExample 1751-(3-(4-Chloro-phenyl)-1-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-but-2-enyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1761-(3-(4-Chloro-phenyl)-1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1771-(3-(4-Chloro-phenyl)-1-{5-[4-(2-methoxy-phenyl)-piperazin-1-yl]-pentyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1781-(3-(4-Chloro-phenyl)-1-{6-[4-(2-methoxy-phenyl)-piperazin-1-yl]-hexyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1792-[1-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethoxy]-acetamideExample 180[1-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethoxy]-aceticacid Example 181[1-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-2-(4-o-tolyl-piperazin-1-yl)-ethoxy]-acetonitrileExample 1821-[1-{3-[4-(2-Bromo-benzenesulfonyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1833-(5-(4-Chloro-phenyl)-2-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-2H-pyrazol-3-yl)-propionicacid methyl ester Example 1842-(4-{3-[3-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-indazol-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 1852-(4-{3-[3-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-indazol-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-phenolExample 1863-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid dimethylamide Example 1871-[1-[2-Azido-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1881-[1-[2-Amino-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1891-{3-(4-Chloro-phenyl)-1-[2-methylamino-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 1903-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 1913-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-indazol-5-oneethylene ketal Example 1921-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 1931-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1942-(4-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 1951-[1-{3-[4-(2-Chloro-benzenesulfonyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 1961-(3-(4-Chloro-2-fluoro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 1972-(4-{3-[5-Acetyl-3-(4-chloro-2-fluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 1981-[3-(4-Chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 1991-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-2-phenyl-ethanoneExample 2001-[3-(4-Chloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2011-[1-{3-[4-(2-Amino-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 202N-[2-(4-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamideExample 203N-[2-(4-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-phenyl]-acetamideExample 2041-[2-(4-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-phenyl]-3-isopropyl-ureaExample 2053-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 2063-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid hydrazide Example 2072-(4-{3-[5-Acetyl-3-(4-phenoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2083-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid phenethyl-amide Example 2093-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid (4-methoxy-phenyl)-amide Example 2103-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbothioicacid methylamide Example 2112-(4-{3-[5-Acetyl-3-(4-chloro-3-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2121-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid ethylamide Example 213N-(5-{5-Acetyl-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-chloro-phenyl)-methanesulfonamideExample 2141-{3-(4-Chloro-phenyl)-1-[2-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2152-(4-{3-[5-Acetyl-3-(4-trifluoromethylsulfanyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2162-(4-{3-[5-Acetyl-3-(3-amino-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2173-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide Example 2183-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid phenylamide Example 2191-[3-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2201-[3-(4-Iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2212-(4-{3-[5-Acetyl-3-(4-methanesulfonyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2221-[1-{2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-methanesulfonyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2231-[3-(4-Iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2241-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide Example 2251-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methyl ester Example 2261-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 227N-[5-(5-Acetyl-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-chloro-phenyl]-methanesulfonamideExample 2281-(5-{5-Acetyl-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-chloro-phenyl)-3-ethyl-ureaExample 2291-[5-(5-Acetyl-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-chloro-phenyl]-3-ethyl-ureaExample 230N-(5-{5-Acetyl-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-chloro-phenyl)-acetamideExample 231 Acetic acid2-[5-acetyl-3-(3-amino-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-[4-(2-cyano-phenyl)-piperazin-1-ylmethyl]-ethylester Example 232N-[5-(5-Acetyl-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-chloro-phenyl]-acetamideExample 233N-[2-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-(4-o-tolyl-piperazin-1-ylmethyl)-ethyl]-methanesulfonamideExample 2341-{3-(4-Chloro-phenyl)-1-[2-(2-pyridin-2-yl-ethylamino)-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 2351-{3-(4-Chloro-phenyl)-1-[2-(2-dimethylamino-ethylamino)-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanoneExample 236 Carbonic acid2-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-(4-o-tolyl-piperazin-1-ylmethyl)-ethylester methyl ester Example 237 Carbamic acid2-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-1-(4-o-tolyl-piperazin-1-ylmethyl)-ethylester Example 2383-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-indazol-5-oneExample 2393-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indazol-5-olExample 2403-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-indazol-5-oneoxime Example 2411-[5-Ethanesulfonyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2421-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methyl ester Example 2431-[5-(4-Chloro-benzenesulfonyl)-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2441-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide Example 2451-[3-(4-Iodo-phenyl)-5-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-olExample 2461-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonitrileExample 2474-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazine-1-carboxylicacid o-tolylamide Example 2484-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazine-1-carboxylicacid (2-methoxy-phenyl)-amide Example 2492-(4-{3-[5-Acetyl-3-(3-chloro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2502-(4-{3-[5-Acetyl-3-(3-fluoro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2512-(4-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-ylmethyl)-benzonitrileExample 2521-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-benzyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2532-(4-{3-[5-Acetyl-3-(4-bromo-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2543-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxamidineExample 2552-(4-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2562-(4-{3-[5-Acetyl-3-(3,4-difluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2572-(4-{3-[5-Acetyl-3-(3,5-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2582-{4-[3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-(2-morpholin-4-yl-ethoxy)-propyl]-piperazin-1-yl}-benzonitrileExample 2592-(4-{2-Hydroxy-3-[3-(4-iodo-phenyl)-5-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrileExample 2602-(4-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 261N-[4-(5-Acetyl-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-acetamideExample 2622-(4-{3-[5-Acetyl-3-(4-bromo-3-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2631-(3-(3-Chloro-4-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2641-[1-{3-[4-(2-Azido-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2652-(4-{3-[5-Acetyl-3-(3-azido-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrileExample 2665-Methanesulfonyl-1-[3-(4-o-tolyl-piperazin-1-yl)-propyl]-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine Example 2675-Methanesulfonyl-1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2681-[1-{2-Hydroxy-3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2693-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 2703-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2711-(3-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2723-(4-Bromo-phenyl)-5-methanesulfonyl-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2733-(3,4-Dichloro-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 2743-(4-Bromo-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonicacid amide Example 2751-(3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanoneExample 2763-(3,4-Dichloro-phenyl)-5-methanesulfonyl-1-{3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2773-(4-Bromo-phenyl)-1-{3-[4-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2781-[1-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2791-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2801-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester Example 2811-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 2821-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-ureaExample 283[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-ureaExample 284[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-carbamicacid methyl ester Example 2851-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-3-methyl-ureaExample 286N-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamideExample 2871-[4-(2,6-Dimethyl-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 2881-[1-{3-[4-(2,6-Dimethyl-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 2892-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-isophthalonitrileExample 2902-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-isophthalonitrileExample 2911-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 2921-[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 2933-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzoicacid methyl ester Example 2943-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)—N-methyl-benzamideExample 295[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-morpholin-4-yl-methanoneExample 2961-[4-(2-Chloro-6-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 2973-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-N-pyridin-4-ylmethyl-benzamideExample 2992-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-nitro-benzoicacid methyl ester Example 3002-(4-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-3-nitro-benzoicacid methyl ester Example 3013-Acetylamino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzoicacid methyl ester Example 3022-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-methanesulfonylamino-benzoicacid methyl ester Example 3032-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-nitro-benzamideExample 3042-(4-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-3-(3-methyl-ureido)-benzoicacid methyl ester Example 3051-[4-(2,6-Dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-olExample 3061-[1-{3-[4-(2,6-Dinitro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3071-[1-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3081-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 3091-[1-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethylsulfanyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3101-[1-{3-[4-(3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3112-(4-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-azido-propyl}-piperazin-1-yl)-benzonitrileExample 3121-[1-{2-Hydroxy-3-[4-(6-nitro-benzothiazol-2-yl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3131-[1-{2-Hydroxy-3-[4-(6-methoxy-benzothiazol-2-yl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneExample 3141-{3-[4-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineExample 3151-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid amide

TABLE 3 EXAMPLE IC₅₀ (μM) 103 2.1 109 1.2 114 1.1 120 12 121 4.3 123 1.9126 7.4 131 2.2 135 1.4 137 0.98 139 0.71 140 0.53 141 1.4 143 0.35 1480.63 149 0.86 150 1.8 156 2.9 159 6.2 164 1.9 167 4.9 170 4.5 174 1.4176 1.6 181 1.7 185 8.4 190 0.26 192 0.79 193 0.33 195 3.3 196 1.9 1991.6 205 0.95 208 1.5 211 0.16 214 1.9 216 1.3 219 10 221 0.82 223 0.23224 0.14 228 2.7 230 0.81 237 1.5 238 3.6 245 0.44 247 4.9 249 0.47 2514.6 255 0.40 258 0.39 260 0.24 262 0.29 266 0.19 267 0.22 270 1.8 2720.15 277 2.8 278 0.19 281 2.5 283 0.08 285 0.04 287 0.20 289 0.15 2930.14 296 0.48 302 0.07 306 0.34 310 0.40 311 2.1 312 0.77

F. OTHER EMBODIMENTS

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

1. A compound of formula (I) below:

wherein: R¹ is hydrogen, azido, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅alkyl, C₂₋₅ alkenyl, cyano, nitro, R⁷R⁸N, C₂₋₈ acyl, R⁹OC═O, R¹⁰R¹¹NC═O,or R¹⁰R¹¹NSO₂; or R¹ is taken together with W as described below; R² ishydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅haloalkyl, cyano, or R⁴⁸R⁴⁹N; alternatively, R¹ and R² can be takentogether to form an optionally substituted 5- to 7-membered carbocyclicor heterocyclic ring, which ring may be unsaturated or aromatic; each ofR³ and R⁴ is independently hydrogen or C₁₋₅ alkyl; each of R⁵ and R⁶ isindependently hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₁₋₅ alkoxy, C₁₋₅alkylthio, halogen, or a 4-7 membered carbocyclyl or heterocyclyl;alternatively, R⁵ and R⁶ are taken together to form a 5- to 7-memberedcarbocyclic or heterocyclic ring, which ring is unsaturated or aromatic,and which ring is optionally substituted with between one and threesubstituents independently selected from halo, cyano, amino, nitro, R⁴⁰,R⁴⁰O—, R⁴⁰S—, R⁴⁰O(C₁₋₅ alkylene)-, R⁴⁰O(C═O)—, R⁴⁰(C═O)—, R⁴⁰(C═S)—,R⁴⁰(C═O)O—, R⁴⁰O(C═O)(C═O)—, R⁴⁰SO₂, NHR⁶²(C═NH)—, NHR⁶²SO₂—, andNHR⁶²(C═O)—; R⁴⁰ is H, C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl, benzyl,phenethyl, C₁₋₅ heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, amino,or mono- or di(C₁₋₅ alkyl)amino, or R⁵⁸OR⁵⁹—, wherein R⁵⁸ is H, C₁₋₅alkyl, C₂₋₅ alkenyl, phenyl, benzyl, phenethyl, C₁₋₅ heterocyclyl, or(C₁₋₅ heterocyclyl)C₁₋₆ alkylene and R⁵⁹ is C₁₋₅ alkylene, phenylene, ordivalent C₁₋₅ heterocyclyl; and R⁶² can be H in addition to the valuesfor R⁴⁰; R⁷ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl,C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R²⁷OC═O, R²⁸R²⁹NC═O, R²⁷SO, R²⁷SO₂,or R²⁸R²⁹NSO₂; R⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅heterocyclyl; alternatively, R⁷ and R⁸ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic; R⁹ is C₁₋₅ alkyl, phenyl, naphthyl,or C₁₋₅ heterocyclyl; R²¹ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl,naphthyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R³⁰OC═O, R³¹R³²NC═O,R³⁰SO, R³⁰SO₂, or R³¹R³²NSO₂; R²² is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,phenyl, or C₁₋₅ heterocyclyl; alternatively, R²¹ and R²² are takentogether to form an optionally substituted 4- to 7-membered heterocyclicring, which ring is saturated, unsaturated or aromatic; each of R²³,R²⁶, R²⁷, R³⁰, R³³, R⁴⁴, R⁴⁵, and R⁵⁰ is C₁₋₅ alkyl, phenyl, naphthyl,or C₁₋₅ heterocyclyl; R²⁴ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl,naphthyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R³³OC═O, R³⁴R³⁵NC═O,R³³SO, R³³SO₂, or R³⁴R³⁵NSO₂; R²⁵ is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl,phenyl, or C₁₋₅ heterocyclyl; alternatively, R²⁴ and R²⁵ are takentogether to form an optionally substituted 4- to 7-membered heterocyclicring, which ring is saturated, unsaturated or aromatic; each of R¹⁰ andR¹¹ is independently hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl, or C₁₋₅heterocyclyl; alternatively, R¹⁰ and R¹¹ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic; each of R²⁸, R²⁹, R³¹, R³², R³⁴,R³⁵, R⁴⁶, R⁴⁷, R⁵¹ and R⁵² is independently hydrogen, C₁₋₅ alkyl,phenyl, or C₁₋₅ heterocyclyl; alternatively, R²⁸ and R²⁹, R³¹ and R³²,R³⁴ and R³⁵, R⁴⁶ and R⁴⁷, or R⁵¹ and R⁵², independently, can be takentogether to form an optionally substituted 4- to 7-membered heterocyclicring, which ring may be saturated, unsaturated or aromatic; n is 2; Grepresents C₃₋₆ alkenediyl or C₃₋₆ alkanediyl, optionally substitutedwith hydroxy, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo, hydroximino,CO₂R⁶⁰, R⁶⁰R⁶¹NCO₂, (L)-C₁₋₄ alkylene-, (L)-C₁₋₅ alkoxy, N₃, or[(L)-C₁₋₅ alkylene]amino; each of R⁶⁰ and R⁶¹ is independently hydrogen,C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, phenethyl, or C₁₋₅heterocyclyl; alternatively, R⁶⁰ and R⁶¹ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic; L is amino, mono- or di-C₁₋₅alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, orpiperazinyl, where available ring nitrogens may be optionallysubstituted with C₁₋₅ alkyl, benzyl, C₂₋₅ acyl, C₁₋₅ alkylsulfonyl, orC₁₋₅ alkyloxycarbonyl; X is nitrogen or R¹²C; Y is nitrogen or R¹³C; Zis nitrogen or R¹⁴C; R¹² is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl,C₂₋₅ alkenyl, cyano, nitro, R²¹R²²N, C₂₋₈ acyl, C₁₋₅ haloalkyl, C₁₋₅heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R²³OC═O, R²³O(C═O)NH—,R²³SO, R²²NHCO—R²²NH(C═O)NH—, R²³(C₁₋₄ alkylene)NHCO—, R²³SO₂, orR²³SO₂NH—; R¹³ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅alkenyl, cyano, nitro, R⁴²R⁴³N, C₂₋₈ acyl, C₁₋₅ haloalkyl, C₁₋₅heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R⁴⁴OC═O, R⁴⁴O(C═O)NH—,R⁴⁴SO, R⁴³NHCO—R⁴³NH(C═O)NH—, R⁴⁴(C₁₋₄ alkylene)NHCO—, R⁴⁴SO₂, orR⁴⁴SO₂NH—; R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅alkenyl, cyano, nitro, R²⁴R²⁵N, C₂₋₈ acyl, C₁₋₅ haloalkyl, C₁₋₅heterocyclyl, (C₁₋₅ heterocyclyl)C₁₋₅ alkylene, R²⁶OC═O, R²⁶O(C═O)NH—,R²⁶SO, R²⁵NHCO—R²⁵NH(C═O)NH—, R²⁶(C₁₋₄ alkylene)NHCO—, R²⁶SO₂, orR²⁶SO₂NH—; alternatively, R¹² and R¹³ or R¹² and R² or R¹³ and R¹⁴ aretaken together to form an optionally substituted 5- to 6-memberedcarbocyclic or heterocyclic ring, which ring is unsaturated or aromatic;Ar represents a monocyclic or bicyclic aryl or heteroaryl ring,optionally substituted with between 1 and 3 substituents selected fromhalogen, C₁₋₅ alkoxy, C₁₋₅ alkyl, C₂₋₅ alkenyl, cyano, azido, nitro,R¹⁵R¹⁶N, R¹⁷SO₂, R¹⁷S, R¹⁷SO, R¹⁷OC═O, R¹⁵R¹⁶NC═O, C₁₋₅ haloalkyl, C₁₋₅haloalkoxy, C₁₋₅ haloalkylthio, and C₁₋₅ alkylthio; R¹⁵ is hydrogen,C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl,aroyl, R⁵³OC═O, R⁵⁴R⁵⁵NC═O, R⁵³S, R⁵³SO, R⁵³SO₂, or R⁵⁴R⁵⁵NSO₂; R¹⁶ ishydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, benzyl, or C₁₋₅heterocyclyl; alternatively, R¹⁵ and R¹⁵ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic; each of R¹⁷ and R⁵³ is C₁₋₅ alkyl,phenyl, or C₁₋₅ heterocyclyl; each of R⁵⁴ and R⁵⁵ is independentlyhydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl, benzyl, or C₁₋₅heterocyclyl; alternatively, R⁵⁴ and R⁵⁵ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic; W represents SO₂, C═O, CHR²⁰, or acovalent bond; or W and R¹, taken together with the 6-membered ring towhich they are both attached, form one of the following two formulae:

 wherein X_(a) is O, S, or N; and X_(b) is O, S or SO₂; R²⁰ is hydrogen,C₁₋₅ alkyl, phenyl, benzyl, naphthyl, or C₁₋₅ heterocyclyl; R⁴² ishydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, naphthyl, C₁₋₅ heterocyclyl,C₂₋₈ acyl, aroyl, R⁴⁵OC═O, R⁴⁶R⁴⁷NC═O, R⁴⁵SO, R⁴⁵SO₂, or R⁴⁶R⁴⁷NSO₂; R⁴³is hydrogen, C₁₋₅ alkyl, C₃₋₅ alkenyl, phenyl, or C₁₋₅ heterocyclyl;alternatively, R⁴² and R⁴³ are taken together to form an optionallysubstituted 4- to 7-membered heterocyclic ring, which ring is saturated,unsaturated or aromatic; R⁴⁴ is C₁₋₅ alkyl, C₂₋₅ alkenyl, phenyl,naphthyl, or C₁₋₅ heterocyclyl; R⁴⁸ is hydrogen, C₁₋₅ alkyl, C₃₋₅alkenyl, phenyl, naphthyl, C₁₋₅ heterocyclyl, C₂₋₈ acyl, aroyl, R⁵⁰OC═O,R⁵¹R⁵²NC═O, R⁵⁰SO, R⁵⁰SO₂, or R⁵¹R⁵²NSO₂; R⁴⁹ is hydrogen, C₁₋₅ alkyl,C₃₋₅ alkenyl, phenyl, or C₁₋₅ heterocyclyl; alternatively, R⁴⁸ and R⁴⁹are taken together to form an optionally substituted 4- to 7-memberedheterocyclic ring, which ring is saturated, unsaturated or aromatic; andwherein each of the above hydrocarbyl or heterocarbyl groups, unlessotherwise indicated, and in addition to any specified substituents, isoptionally and independently substituted with between 1 and 3substituents selected from methyl, halomethyl, hydroxymethyl, halo,hydroxy, amino, nitro, cyano, C₁₋₅ alkyl, C₁₋₅ alkoxy, —COOH, C₂₋₆ acyl,[di(C₁₋₄ alkyl)amino]C₂₋₅ alkylene, [di(C₁₋₄ alkyl)amino]C₂₋₅alkyl-NH—CO—, and C₁₋₅ haloalkoxy; or a pharmaceutically acceptablesalt, ester, or amide thereof.
 2. A compound of claim 1, wherein R¹ ishydrogen, halogen, C₁₋₅ alkoxy, hydroxy, C₁₋₅ alkyl, cyano, nitro,R⁷R⁸N, C₂₋₈ acyl, or R¹⁰R¹¹NSO₂.
 3. A compound of claim 2, wherein R¹ ishalogen, cyano, nitro, R⁷R⁸N, or R¹⁰R¹¹NSO₂.
 4. A compound of claim 1,wherein R² is hydrogen.
 5. A compound of claim 1, wherein each of R³ andR⁴ is independently hydrogen or C₁₋₃ alkyl.
 6. A compound of claim 5,wherein one of R³ and R⁴ is hydrogen.
 7. A compound of claim 6, whereineach of R³ and R⁴ is hydrogen.
 8. A compound of claim 1, wherein one ofR⁵ and R⁶ is hydrogen and the other is a 5-7 membered carbocyclyl orheterocyclyl, optionally substituted.
 9. A compound of claim 1, whereinR⁵ and R⁶ taken together form a six-membered heterocyclyl.
 10. Acompound of claim 8, wherein R⁵ and R⁶ taken together form pyridinyl,pyrimidinyl, or piperazinyl, optionally N-substituted withR⁴⁰O(C═O)(C═O)—, R⁴⁰SO₂, R⁴⁰NHCO₂, R⁴⁰(C═O)— or R⁴⁰N(C═O)—.
 11. Acompound of claim 1, wherein each of R⁷, R⁸, R²¹, R²², R²⁴, and R²⁵ isindependently hydrogen or C₁₋₅ alkyl; or, independently, each of R⁷ andR⁸, R²¹ and R²², and R²⁴ and R²⁵ are taken together to form anoptionally substituted 4- to 7-membered heterocyclic ring, which ring issaturated, unsaturated or aromatic.
 12. A compound of claim 11, whereinat least one of R⁷ and R⁸, R²¹ and R²², and R²⁴ and R²⁵ taken together,is morpholinyl, piperidinyl, or pyrrolidinyl.
 13. A compound of claim 1,wherein R⁹, R²³, R²⁶, and R²⁷ are each independently C₁₋₅ alkyl.
 14. Acompound of claim 1, wherein G is C₃₋₄ alkanediyl, optionallysubstituted with hydroxy, (L)-C₁₋₅ alkyloxy-, or [(L)-C₁₋₅alkylene]amino-.
 15. A compound of claim 14, wherein G is C₃ alkanediyl,optionally substituted with hydroxy, (L)-C₁₋₅ alkyloxy-, or [(L)-C₁₋₅alkylene]amino-.
 16. A compound of claim 1, wherein X is nitrogen.
 17. Acompound of claim 1, wherein Y is CR¹³.
 18. A compound of claim 1,wherein Z is CR¹⁴.
 19. A compound of claim 18, wherein X is CH.
 20. Acompound of claim 1, wherein R¹² is hydrogen, R²³O(C═O)NH—,R²²NH(C═O)NH—, R²³SO₂NH, R²³SO, or R²³SO₂, and R¹³ is hydrogen,R⁴⁴O(C═O)NH—, R⁴³NH(C═O)NH—, R⁴⁴SO₂NH, R⁴⁴SO, or R⁴⁴SO₂.
 21. A compoundof claim 1, wherein R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅ alkyl,cyano, nitro, R²⁶O(C═O)NH—, R²⁵NH(C═O)NH—, R²⁶SO₂NH, or R²⁴R²⁵N.
 22. Acompound of claim 21, wherein R¹⁴ is halogen, R²⁶O(C═O)NH—,R²⁵NH(C═O)NH—, R²⁶SO₂NH, or R²⁴R²⁵N.
 23. A compound of claim 1, whereinAr represents a monocyclic ring, optionally substituted with between 1and 2 substituents selected independently from halogen, C₁₋₅ alkyl,cyano, nitro, R¹⁵R¹⁶N, CF₃, and OCF₃.
 24. A compound of claim 23,wherein Ar is a six membered ring substituted with between 1 and 2substituents selected from halo, CF₃, and OCF₃, said substitutent orsubstitutents being at the 4-position or at the 3- and 4-positions,respectively.
 25. A compound of claim 1, wherein W is SO₂, C═O, orCHR²⁰.
 26. A compound of claim 1, wherein W is a covalent bond.
 27. Acompound of claim 1, wherein W and R¹ taken together are formula (I)(a).28. A compound of claim 1, wherein W and R¹ taken together are formula(I)(b).
 29. A compound of claim 1, wherein one of R³ and R⁴ is hydrogen;Ar represents a monocyclic ring, optionally substituted with between 1and 2 substituents selected from halogen, C₁₋₅ alkyl, cyano, nitro,R¹⁵R¹⁶N, CF₃, and OCF₃; R¹² is hydrogen, R²³SO, or R²³SO₂; R¹³ ishydrogen, R⁴⁴SO, or R⁴⁴SO₂; R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅alkyl, cyano, nitro, or R²⁴R²⁵N; and G is C₃₋₄ alkanediyl, optionallysubstituted with hydroxy, C₁₋₃ alkyl, (L)-C₁₋₅ alkyloxy, or [(L)-C₁₋₅alkylene]amino-.
 30. A compound of claim 1, wherein each of R³ and R⁴ ishydrogen; Ar represents a six membered ring, optionally substituted withbetween 1 and 2 substituents selected from halogen, C₁₋₅ alkyl, cyano,nitro, R¹⁵R¹⁶N, CF₃, and OCF₃; R¹² is hydrogen, R²³SO, or R²³SO₂; R¹³ ishydrogen, R⁴⁴SO, or R⁴⁴SO₂; R¹⁴ is hydrogen, halogen, C₁₋₅ alkoxy, C₁₋₅alkyl, cyano, nitro, or R²⁴R²⁵N; and G is C₃ alkanediyl, optionallysubstituted with hydroxy, (L)-C₁₋₅ alkyloxy-, or (L)-C₁₋₅ alkylamino.31. A compound of claim 30 wherein Ar is phenyl.
 32. A compound of claim31, wherein W and R¹ taken together are formula (I)(b).
 33. Apharmaceutical composition comprising a compound of claim 1, 30, or 31and a pharmaceutically acceptable carrier.
 34. A method for treating anautoimmune disease, or inhibiting the progression of an autoimmunedisease, in a subject, said method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of claim 1, 30, or 31, wherein theautoimmune disease is selected from lupus, rheumatoid arthritis, andasthma.
 35. A method of claim 34, wherein the autoimmune disease isasthma.
 36. A method for treating the proteolytic activity of humancathepsin S comprising contacting human cathepsin S with a compound ofclaim
 1. 37. A method of claim 36, wherein the human cathepsin S is in ahuman subject.
 38. A method of claim 37, wherein the human subject issuffering from an autoimmune disease selected from lupus, rheumatoidarthritis, and asthma.